Universit de Montral

The Remote Clinical Trials Model

Digital Health Strategies to drive Patient Centricity

by
Hassan Kadhim

Universit de Montral
Facult de Pharmacie

Thesis presented to the Faculty of Pharmacy

to obtain a Masters degree
in Pharmaceutical Sciences
option Drug Development

April 2016

Hassan Kadhim, 2016

(This page is intentionally left blank)

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Abstract
The pharmaceutical industry is currently undergoing a wave of major strategic transformations
in terms of comprehensive future vision. Indeed, several recent developments in the industry will likely
lead towards a transition in the business culture and strategic approach of different aspects managed by
pharmaceutical companies. The patent cliff is causing revenue losses in the pharmaceutical industry,
forcing it to look at new ways of leading its business. In 2012, the expiration of drug patents produced
more than 28 billion dollars in lost revenues (1). This loss in revenues, combined with the growing
compliance requirements of regulatory agencies for the approval of innovative new products, has
created the urgent need to reduce research and development costs in the pharmaceutical industry.
Therefore, several companies in the industry are looking for new ways of getting significant
reductions in cost and time, without reducing the quality of research. In the year 2000, it was estimated
that the cost of producing a drug from research to market was about 800 million dollars (2). By
considering the economic evolution since then, the costs are estimated to rise to between 1.3 and 1.7
billion dollars in 2009 (3). This cost comprises all the preclinical research (R & D) activities as well as
all the clinical research (phases I, II, III). In the field of clinical research, a large multicenter clinical
trial can cost up to $ 300 million, including the implementation, design and monitoring of the clinical
trial (4). These exorbitant development costs are transmitted to patients in the price of new medicines
and thereby add a fairly high price tag to a health system that is already quite expensive. With the
recent "Patient Protection Affordable Care Act" (PPACA) passed in the United States, there is constant
pressure on the pharmaceutical industry to reduce the cost of innovative pharmaceutical products,
while maintaining the quality and safety of these products. In addition, one of the key changes brought
about by the PPACA is that by the year 2014, patient information will be processed and collected
electronically (Electronic Health Records). It is anticipated that a fully digital health ecosystem will
result through the mass digitization of patient records, thus facilitating the collection and access to
clinical data from patients across the United States. To this is added a number of emerging
technologies, such as smartphones, wearables and sensors and social networking platforms, creating
new opportunities for the collection of clinical data and patient engagement in clinical research.
Finally, refund policies in healthcare systems worldwide increasingly emphasize on outcome-based
reimbursement, thus generating more pressure among clinicians and their partners (including the
pharmaceutical industry) to generate more efficient and specific medicines.
These challenges have pushed the pharmaceutical industry to find new ways to innovate in the
field of clinical research, an area that is usually highly regulated and therefore slow to adopt
innovation. Additionally, the combination of all these trends brings the pharmaceutical industry to

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focus significantly on becoming more patient-centric in clinical research. Since enabling technologies
are already present, innovating and improving certain aspects of clinical trials proves to be an exciting
and promising outcome for the pharmaceutical industry, in its quest towards patient centricity.
Recently, the pharmaceutical giant Pfizer introduced an innovative new concept in clinical
research: a virtual clinical trial. REMOTE (Research on Electronic Monitoring of Overactive bladder
Treatment Experience) is the first randomized Phase IV virtual clinical trial involving an
investigational new drug (IND), and gives rise to new opportunities in clinical research. The purpose of
REMOTE was to evaluate the efficacy and safety of Detrol LA (tolterodine tartrate), a treatment for
patients with overactive bladder. The company wanted to determine whether the particular virtual
clinical trial could provide comparable results to the traditional clinical trial, with the same parameters
and the same endpoints. The REMOTE trial is consistent with the mission of the FDA to improve the
quality and efficiency of clinical trials (CTTI) (7). The potential success of this new approach would
bring several benefits to the pharmaceutical industry. Among these benefits is an anticipated reduction
in clinical research costs, efficient and targeted patient recruitment, and access to a larger number of
patients since they would no longer be connected to a specific clinical center. Additionally, a
considerable improvement in data collection, data analysis and clinical monitoring during the clinical
trial is also anticipated. Finally, improving the overall patient experience remains one of the most
important benefits anticipated by this approach, aligning with the concept of Patient Centricity.
The bold and innovative new approach initiated by Pfizer in collaboration with the FDA is
prompting others in the pharmaceutical industry to consider and evaluate new ways of conducting
clinical research for new investigational drugs. We propose to develop a full feasibility study on the
Remote Trial Model as a new concept in clinical research, from the recruitment and enrollment of
patients, to the collection and monitoring of clinical data. This work will focus on describing the
model, and discuss several considerations for necessary adaptations of the regulatory, legal, clinical
and technological contexts in order to promote this new approach. It is estimated that by 2030, the
pharmaceutical industry would have fully embraced this new concept. In the meantime, considerable
efforts need to be spent to clarify the use and relevance of this concept for the pharmaceutical industry.

Keywords : Pharmaceutical industry, Clinical Research, Clinical Trials, Clinical Studies,

Smartphones, Smart technologies, Technology in Clinical Trials, Healthcare, remote clinical
trial model, innovation.

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Table of Contents
Abstract ....................................................................................................................................... ii

Table of Contents ....................................................................................................................... iv

List of tables ............................................................................................................................... vi

List of figures ............................................................................................................................ vii

List of abbreviations ................................................................................................................ viii

Acknowledgements .................................................................................................................... xi

1. Introduction ......................................................................................................................... 1

1.1 Trends in Clinical Research Patient Centricity ........................................................ 2

1.1.1 Pfizers REMOTE study ......................................................................................... 2
1.2 Project Rationale and Scope Boehringer Ingelheim ................................................ 3
2. Clinical Research in the pharmaceutical industry............................................................... 5

2.1 Current Trends in the industry leading to Patient Centricity ...................................... 7

2.1.1 Trends around the emergence of Mobile Consumer Health Technology ............... 7
2.1.2 Trends surrounding the pharmaceutical industry.................................................... 8
2.1.3 Trends surrounding the global healthcare industry................................................. 9
2.2 Patient Centricity vision and benefits for the industry........................................... 10
Methodology ..................................................................................................................... 12
Anticipated Results ........................................................................................................... 13
3. Remote Clinical Trials a model for the industry............................................................ 14

3.1 Ethical and Regulatory contexts for the Remote Clinical Trial ................................ 15
3.1.1 Ethical context: ICH E6 and ICH E8 .................................................................... 15
3.1.2 Regulatory context FDA .................................................................................... 16
3.1.3 Regulatory context Health Canada .................................................................... 19
3.2 Components of the Remote Clinical Trial model ..................................................... 20
3.2.1 Patient Recruitment and Retention in clinical research ........................................ 21
3.2.2 Electronic Informed Consent (eConsent).............................................................. 27

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 3.2.3 Electronic Data Capture (eSource, ePROs, Wearables) ....................................... 32
3.2.4 Telemedicine, Monitoring, and Drug Adherence ................................................. 42
3.3 Integral representation of the Remote Clinical Trial model ..................................... 53
3.3.1 Diagram of the Remote Clinical Trial model ....................................................... 53
3.3.2 Alternative to the Remote Clinical Trial model: the Hybrid model ..................... 59
3.3.3 Comparison between the Remote and Traditional Clinical Trial models in clinical
research ............................................................................................................................. 61
4. Discussion ......................................................................................................................... 63

4.1 Practical Considerations for the application of the Remote Clinical Trial model .... 63
4.1.1 Clinical Considerations ......................................................................................... 63
4.1.2 Regulatory, Ethical and Legal Considerations...................................................... 69
4.1.3 Technological Considerations............................................................................... 72
4.1.4 Change Management Considerations for Clinical Operations departments ......... 74
4.2 Applying the model Case Study ............................................................................ 76
4.2.1 Economic Impact of the Remote Trial Model ...................................................... 83
4.3 Perspectives in Remote Clinical Trial Conduct within the industry ......................... 88
5. Conclusion ........................................................................................................................ 92

Bibliography ............................................................................................................................. 94

Annexes................................................................................................................................... 101

Annex I: List of Therapeutic Areas .................................................................................... 101

Annex II: Survey on the perceptions around the Remote Clinical Trial model.................. 103

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List of tables
Table 1: Comparison between the years 1999 and 2005 for various aspects of clinical trial
conduct ........................................................................................................................................ 6
Table 2: Comparison between the remote trial model and the traditional trial model in clinical
research, for each of the components ........................................................................................ 62
Table 3: Study Synopsis with all expected procedures per visit (Part I) .................................. 77
Table 4: Study Synopsis with all expected procedures per visit (Part II) ................................. 78
Table 5: Study synopsis by the remote trial model with planned activities for each visit (Part I)
................................................................................................................................................... 82
Table 6: Study synopsis by the remote trial model with planned activities for each visit (Part
II)............................................................................................................................................... 82
Table 7: Analysis of the different clinical research costs, per phase of clinical research......... 83
Table 8: Analysis and comparison of the costs, productivity and patient convenience between
the traditional and remote clinical trial models, for the Phase IV study described earlier. ...... 85
Table 9: Analysis of the perspectives of different stakeholders in clinical research towards the
implementation of the remote trial components and the remote trial model. ........................... 89

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List of figures
Figure 1 - Dr. Schnippers declaration appearing on Twitter in 2014 ........................................ 5
Figure 2: Integral representation of the remote clinical trial model, with one central
coordinating site ........................................................................................................................ 53
Figure 3: Integral representation of the hybrid model, with the presence of multiple sites ..... 60

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List of abbreviations
ALCOA: Attributable, Legible, Contemporaneous, Original and Accurate
BI: Boehringer-Ingelheim
BDI: Baseline Dyspnea Index
BIDMC: Beth Israel Deaconess Medical Center (United States)
BMHCI: Business Model & HealthCare Innovation (Boehringer-Ingelheim)
BYOD: Bring Your Own Device
CAT: COPD Assessment Test
CFR: Code of Federal Regulations (United States)
CHI: Cambridge Healthtech Institute
CRA: Clinical Research Associate
CRF: Case Report Form
CRO: Clinical/Contractual Research Organization
COPD: Chronic Obstructive Pulmonary Disease
CTTI: Clinical Trial Transformation Initiative (United States)
DHHS: Department of Health and Human Services (United States)
eCRF: electronic Case Report Form
ePRO: electronic Patient-Reported Outcomes
EHR: Electronic Health Records
EMA: European Medicines Agency (Europe)
FDA: Food and Drug Administration (United States)
FEV1: Forced Expiratory Volume in 1 minute
FVC: Forced Vital Capacity
GCP: Good Clinical Practices
GP: General Practitioner
HC: Health Canada
HIPAA: Health Insurance Portability and Accountability Act (United States)
HITECH: Health Information Technology for Economic and Clinical Health Act
ICH: International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use

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IND: Investigational New Drug
IOM: Institute of Medicine (United States)
IoT: Internet of Things
IRB: Institutional Review Board
IT: Information Technology
IVRS: Interactive Voice Response System
KOL: Key Opinion Leader
LTE: Long Term Evolution (Mobile internet network)
NIH: National Institute of Health (United States)
PCORI: Patient-Centered Outcomes Research Institute (United States)
PPACA: Patient Protection and Affordable Care Act (United States)
PRO: Patient-Reported Outcomes
RBM: Risk-Based Monitoring
REMOTE: Research on Electronic Monitoring of Overactive bladder Treatment
Experience (Phase IV clinical study run by Pfizer)
SCOPE: Summit for Clinical Operations Executives
SDV: Source Data Verification
SGRQ: St-Georges Respiratory Questionnaire
SOP: Standard Operating Procedures
TDI: Transition Dyspnea Index
US: United States
WiFi: Wireless Fidelity (wireless internet)
WHO: World Health Organization

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Dedicated to my family, my parents, my spouse and children, a better future, and more health
for generations to come

x
Acknowledgements
I would like to thank everyone who supported me during the formulation of the
concept of virtual clinical research, including distinguished thanks to Dr. Patrick Frankham,
who mentored me throughout the process of research and writing. Special thanks to Craig
Lipset of Pfizer and Michael Tucker of Mytrus that greatly helped me formulate my first ideas.
A big thank you goes to all colleagues from Boehringer Ingelheim that have been really
generous with their time (Samar Darwish, Rebecca Eskew-Griffith, Dr. Martina Flammer, Dr.
Alan Hamilton, Berengre Langellier, Andy Lawton, Dr. Stephanie Ounpuu, Katrin Ong, Dr.
Thomas Rauch, Thomas Reith, Dr. Wolfgang Renz, Dr. Jasmin Saric, Dr. Jeanne Varrone,
Mireille Zerola). Special thanks go to Dr. Leonard Sacks from the FDA who allowed me to get
more insights in regard to regulatory and legal considerations. I would also like to thank
Sylvie Ducharme for her expertise and outlook on the Canadian regulatory side. Special
thanks go to Tom Krohn from the company TrialReach, Bill Gwinn of Optum, Denis Curtin
from mProve and Michael O'Brien of AMC Health. Thanks to all survey respondents on
Perspectives in Remote Patient-Centric Trial Conduct. Also, I would like to thank Mario
Tanguay for his support during the academic process and coordination with the University of
Montreal.

Finally, a big thank you goes to my family, in particular my parents for instilling in me
the spirit of curiosity and resilience needed to complete this journey and my wife and children
who had to endure several hours of dedication and hard work on my part, while not being
available at their side.

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 1. Introduction
Several current factors have led the pharmaceutical industry to reconsider its overall
strategy for research and clinical development.

Economic factors are, arguably, the leading variable in this equation. The patent cliff
phenomenon is largely responsible for a considerable loss of revenue for the pharmaceutical
sector. In 2012, it is estimated that this phenomenon yielded more than 28 billion dollars in
loss of exclusivity (1). This, combined with the growing demands of regulatory agencies
regarding the approval of innovative medicines, justifies the need to reduce the costs of
research and development.

The emergence of several current technologies such as smartphones, social networks

and the Internet of Things (IoT) phenomenon have given birth to novelties like wearables
embedded with biosensors, to possibly promote innovation in clinical research. Combined
with the constant desire of the pharmaceutical industry to improve its image among patients,
this gives birth to a new concept in clinical research named "Patient Centricity". This concept
demonstrates a marked change in the general culture in the pharmaceutical industry, centering
clinical research around the interests of the patient, compared to the current model which
focuses the study on the interests of the clinical site and the sponsor. Indeed, it is becoming
increasingly clear that many pharmaceutical companies are driving their clinical research and
development programs towards the concept of Patient Centricity, incorporating many facets to
enhance the patient's interest first. This includes some initiatives to consult with patient
advocacy organizations by giving them access to the protocol before study startup, others
giving patients their data and results at the end of the study, and others facilitating patient
access and retention in clinical trials, while improving the overall patient experience during
the course of the study. It is especially the latter, improving the overall patient experience,
which is targeted by the concept of Patient Centricity.

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 1.1 Trends in Clinical Research Patient Centricity
The concept of Patient Centricity is not new. A thorough review of the literature proves the
existence of this concept in the field of healthcare since 1980 (8), the term itself appearing
around 2001 (9). The concept took larger proportions during recent years in the field of
clinical research since the creation of the "Patient Protection and Affordable Care Act"
(PPACA) in the United States, and the formation of PCORI (Patient Centered Outcomes
Research Institute). PCORI's mission is "to improve the quality and relevance of evidence
available to help patients, caregivers, clinicians, employers, insurers, and policy makers make
informed health decisions" (10). In 2007, the FDA (Food and Drug Administration) partnered
with Duke University in North Carolina to create CTTI (Clinical Trials Transformation
Initiative), a public-private partnership aimed "to identify and promote practices that will
increase the quality and efficiency of clinical trials" (11). Similar initiatives around the globe
have emerged in recent years to promote better health systems and more effective clinical
research. These initiatives reflect the growing awareness of the pharmaceutical industry and
global health systems to deal with current issues affecting clinical research. Therefore, it is
interesting to observe that the majority of large reputable pharmaceutical companies today
have launched major reform programs to implement Patient Centricity in all aspects of their
business, including clinical research. An important strategy for applying Patient Centricity can
result in the development of new clinical research design concepts facilitated by emerging
digital health technologies, thereby enhancing patients overall experience during clinical trial
conduct.

1.1.1 Pfizers REMOTE study

In 2012, Pfizer introduced an innovative new concept in clinical research to strengthen

the idea of Patient Centricity. Aimed at facilitating clinical research access to patients, Pfizer
undertook the REMOTE study (Research on Electronic Monitoring of Overactive bladder
Treatment Experience), the first completely remote phase IV randomized clinical trial for an
investigational new drug (IND) (7, 64). The purpose of REMOTE was to evaluate the efficacy
and safety of Detrol LA (tolterodine tartrate), a treatment for patients with overactive bladder.
The REMOTE study consisted of online patient recruitment, remote patient data collection

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using medical devices connected to a smartphone and remote data monitoring via an
informatics system approved by the FDA. The study was not reliant on any clinical site. This
innovative concept gave rise to new opportunities in clinical research, including the use of
electronic informed consent technology, the use of medical devices to collect data remotely
via smartphone technology, and patient participation in clinical trials from the comfort of their
homes. The REMOTE trial is consistent with the FDAs mission through the CTTI
organization to improve the quality and efficiency of clinical trials.

1.2 Project Rationale and Scope Boehringer Ingelheim

Boehringer Ingelheim (BI) ranks in the list of largest pharmaceutical companies in the
world and is undoubtedly affected by trends that modulate the industry. Thus, in 2011 the
"Business Model Innovation & HealthCare (BMHCI)" team at BI focused on innovation and
the implementation of new concepts in clinical research, focusing on the concept of site-less
clinical trials, probably inspired by Pfizers REMOTE study. The main goal of their quest
was to discern a way to reduce the costs of clinical research, specifically for the Chronic
Obstructive Pulmonary Disease (COPD) Program in Phase III. In their analysis, BMHCI
examined various issues related to the conduct of clinical trials and provided a preliminary
report to define the foundations needed to establish a more cost-effective and efficient clinical
program. The report proposes to establish a digital health strategy for the use of medical
devices while partnering with a contractual organization (CRO) to conduct the COPD clinical
research program, while eliminating or reducing the role of clinical sites. Following this report
came the "e-trial" initiative, aimed at implementing the recommendations of BMHCI for the
COPD clinical research program. The e-trial team was an interdisciplinary team mandated to
assess the feasibility of the concept of remote clinical trials for the COPD program to advance
a totally remote clinical trial concept or a hybrid between the remote / traditional clinical
model. However, due to the immaturity of the technology space at the time and regulatory
considerations combined with the conservative nature of clinical teams, the e-trial team was
unfortunately unable to convince senior management to adopt an innovative approach to the
large phase III program with COPD, and the e-trial initiative lost sponsorship support.

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 This Master's thesis work was then born, having a mandate to establish a model of
remote clinical study conduct considering the different aspects related to clinical research. In
order to gradually change the operational culture of clinical research conduct, we offer to
revisit the following aspects of clinical research in order to establish a feasible model for
remote clinical trials:
Patient Recruitment and Retention facilitated by emerging digital health technologies
Electronic Informed Consent
Electronic Clinical Data Capture at the source (eDevices, ePRO, wearables)
Telemedicine, Clinical Trial Monitoring and Treatment Adherence
Clinical, Regulatory, Ethical, Legal, Technological and Change Management
considerations related to the Remote Clinical Trial model
Economic Impact of the Remote Clinical Trial model
Perspectives on the Remote Clinical Trial model

Also, given the innovative nature of the Remote Clinical Trial concept, the aim is to apply the
model to an existing clinical trial if possible or a discontinued BI clinical study. The objective
of this initiative is therefore to provide a synopsis of a clinical trial protocol while maximizing
the contribution of components described by the Remote Clinical Trial model.

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 2. Clinical Research in the pharmaceutical industry
The development and conduct of clinical trials remains the gold standard to generate
evidence needed to approve a therapy against a specific therapeutic indication. Conversely, the
evolution of clinical research in complexity and costs over previous decades gave way to a
rigid unsustainable system that fails to meet the growing needs of patients and regulatory
agencies in obtaining the necessary information in a timely manner. Figure 1 illustrates an
interesting recent reflection of Dr. Lowell E. Schnipper from BIDMC (Beth Israel Deaconess
Medical Center) in Boston which summarizes the patients perspective on the state of the
pharmaceutical industry in clinical research.

Figure 1 - Dr. Schnippers declaration appearing on Twitter in 2014

Despite the fact that a statement like this certainly contains a dose of exaggeration, it provides
a window of consideration into the important deficiency in clinical research of our days. In
drawing a parallel with the impact that the Internet of Things (IoT) and its adjacent
technologies has had on other industries, it becomes clear that the pharmaceutical industry is
largely behind in leveraging this opportunity to improve its processes. This trend is even more
striking when one turns to the field of clinical research, which is highly regulated and often
reluctant to bear risks. This paradoxical comparison of the pharmaceutical industry among
other industries is somehow manifested in the growing difficulty in recruiting patients for
participation in clinical trials. The challenges are even more pronounced when trying to find

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treatment-nave patients for clinical research. This problem eventually puts a dent in the
ultimate goal of finding cures to improve the lives of these patients. However, this trend
cannot be attributed to a lack in the discovery of innovative molecules or adequate procedures
for the conduct of clinical protocols. In 2008, a study from Tufts University in Massachusetts
demonstrated the difference between the years 1999 and 2005 in the number of procedures,
the average workload of clinical staff, the average length of protocols and the recruitment and
retention of patients in clinical trials (Table 1) (12). The study revealed an alarming trend for
clinical research: the costs and timelines for clinical trials are rising while recruitment and
retention of patients in clinical studies are declining.

Table 1: Comparison between the years 1999 and 2005 for various aspects of clinical trial conduct

This disconcerting trend, among a few others, pushes the pharmaceutical industry to
rethink its strategy of engaging patients, which is its main stakeholder at the end of the line.
Several initiatives and strategies in recent years have been set up in the industry especially to
temper the effects of this trend and lead the industry into a new era, where clinical research is
placed at a level consistent with the technological opportunities of the 21st century.
Organizations like PCORI, CTTI, Transcelerate and others are aiming to transform clinical
research to promote patient engagement and increase collaboration between different
stakeholders involved in clinical research. These efforts also aim at establishing best practices
and guidelines and creating tools and solutions to tackle several known issues in clinical
research today. It is therefore fathomable that the concept of Patient Centricity, briefly
described in the introduction, becomes a turning point in the strategy for the transformation of

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several companies in the pharmaceutical industry. The objective of this transformation is for
the industry to progress towards an adaptation of clinical research to become more focused
around the patient, and thus hope to increase efficiency, effectiveness and patient satisfaction
and participation in clinical research.

2.1 Current Trends in the industry leading to Patient

Centricity
Three major factors lead the industry to seriously consider adopting the concept of
Patient Centricity. These factors are:

1. Trends around the emergence of Mobile Consumer Health Technology

2. Trends surrounding the pharmaceutical industry

3. Trends surrounding the global healthcare industry

2.1.1 Trends around the emergence of Mobile Consumer Health

Technology

The recent rise of modern technology such as smartphones at the consumer level offers
new opportunities in several industries to interact and engage with their customers. Indeed,
these technologies open up many new channels with consumers through the use of a variety of
smartphone applications available at their fingertips. In a 2015 study by the Pew Research
Center, it was found that 64% of the adult population in the United States owns a smartphone
(13). This revealing statistic is comparable to other developed countries and regions such as
Canada and Europe. Other studies report that 72% of US Internet users (14) and 85% of
European Internet users (15) are turning to the internet to obtain health information. The
ubiquity of smartphones combined with the attitude of Internet users seeking information
relevant to their health present a unique opportunity for healthcare institutions and the
pharmaceutical industry to engage their patients through various digital strategies.

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 Added to this is the growing popularity of social networks with various communities of
patients that cluster around common traits or diseases afflicting them or their close relatives.
Indeed, the ease with which these communities come together and share information about
their conditions opens new avenues that were not present before for patients and the industry.
Thus, several opportunities arise in the industry around patient recruitment and engagement in
clinical research as well as the capture of conversations happening between patients on these
social networks.

Finally, the impending alliance between microchip sensors manufacturers and those of
smart devices gives rise to the establishment of new biometric data capturing methods in a
continuous frequency, opening up even more opportunities for real-world evidence in clinical
research. Certainly, the recent increasing popularity of wearable devices that can capture real-
world data turns out to be a brilliant opportunity for the industry to better engage and facilitate
patients access to clinical research.

All of these technological trends render a sustained effect to disrupt clinical research
conduct in the pharmaceutical, life sciences and healthcare industries.

2.1.2 Trends surrounding the pharmaceutical industry

The patent cliff has directly affected the pharmaceutical industry in recent years. In
2012, it is estimated that this phenomenon was responsible for $28 billion in revenue losses
globally (1). The industry is therefore enticed to seek new ways to counter this trend which
undermines its ability to innovate in finding new treatments to the world populations unmet
medical needs.

Additionally, the pharmaceutical industry is driven by an important compliance

opportunity to increasing regulatory requirements in research, development and manufacturing
of pharmaceutical products. This places significant pressure on the industry to continuously
improve data quality and provide conclusive evidence of the superiority of their treatments
compared to standards of care for specific diseases.

Finally, the perception of a lack of real commitment to their patients and a lack of
transparency with respect to clinical data related to their products leaves the industry with a

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not too decent reputation (16). These symptoms may partly be due to the increasingly visible
trend of resisting to adapt antiquated business practices and processes. Some sales and
marketing practices, as well as a leading perception of expensive prices for pharmaceutical
products also contribute to the perceived negative reputation with the general public. This fact
is further accentuated with the often highly publicized discovery of harmful side effects after a
treatment is placed on the market.

The aggregation of these trends pushes the pharmaceutical industry to seriously

consider a change of vision towards a comprehensive strategy to ensure its survival and
prosperity. This change in strategy is becoming increasingly evident at various operational
levels of the industry, ranging from preclinical and clinical research to sales and marketing
practices, as well as an increase in relationships with patient advocacy organizations.

2.1.3 Trends surrounding the global healthcare industry

The global healthcare domain is also experiencing a wave of trends that are exerting
pressure to adapt its processes and practices. The often exorbitant costs associated with
treatments require many governments to revise their public health management strategy to
better service their citizens. In recent years, a major shift in US healthcare policy led to the
PPACA, showing a willingness of the US government to improve access to the health system.
The various discussions that led to the establishment of this policy gave rise to an increasing
consideration of outcome-based reimbursement from the traditional volume-based fee-for-
service model. This shift in treatment refund policy puts particular emphasis on the various
players in the healthcare field to optimize the recovery of patients after treatment compared to
the previous reimbursement model based on volume. It is predicted that this transition on
reimbursement will lead to an overall reduction in healthcare related costs (17).

The excessive costs related to healthcare can also be attributed to a global pandemic of
chronic diseases afflicting the general world's population. According to a report from the
World Health Organization (WHO), in 2012, chronic conditions were responsible for 68% of
the 56 million deaths across the globe (18). This proportion has been constantly increasing in
recent years, placing chronic conditions at the top of the list of causes of death worldwide.
This trend demonstrates the worldwide recognized effect of an aging population as well as a

9
decrease in the contribution of infectious diseases in overall mortality, previously recognized
as the main cause. With life expectancy increasing compared to previous times, chronic
diseases present a clear challenge to the need of containing overall healthcare costs worldwide.
Therefore, special attention is growing across healthcare systems and health institutions to
mitigate the burden of disease brought by chronic diseases.

Finally, the contribution of technology cannot be ignored as a major trend affecting the
healthcare sector. Indeed, this contribution is not only attributed to technological progress in
the various medical instruments and devices, but also in terms of overall disease and treatment
management through healthcare institutions. The ubiquity of the Internet combined with the
increased capacity of audiovisual data transmission across the web favors the entrance of
telemedicine as a means of diagnosis, monitoring and communication between medical staff
and patients. The adoption of telemedicine in different medical fields brings many practical
benefits to patients, and may be an important factor to reduce costs of treatments. Hence, the
prospective of enabling patients and physicians to benefit from electronic visits (e-visits)
remains a promising avenue for the health sector.

The combined effect of these factors highlights the importance of Patient Centricity in
the pharmaceutical industry and in healthcare. Specifically, the pharmaceutical industry
certainly realizes the need for a change of vision and strategy to maximize the impact of
current opportunities and transform its image and mission towards Patient Centricity.

2.2 Patient Centricity vision and benefits for the industry

Although it is a quite fashionable term these days and can certainly be categorized as a
buzz word, Patient Centricity in itself is not a new concept. A review of the literature
demonstrates that the concept begins to have roots in the field of healthcare in the 1980s, with
several articles claiming the need to adopt an approach more focused on the patient without
formally citing the term Patient Centricity (19, 20).

The term itself appeared in 2001, when the Institute of Medicine (IOM) published a
paper describing the need to take important steps to improve the quality of treatment given to

10
patients in healthcare (9). It is therefore clear that this concept is not new in the field of
healthcare, but it has recently taken more scale in the field of clinical research after the
establishment of the Affordable Care Act (PPACA) in the United States, and with the
formation of PCORI.

The pharmaceutical industry is becoming increasingly interested in this concept and is

trying to establish a gradual cultural shift towards a more patient-centric approach, focusing on
the patient through its various activities.

As part of our research for this work, we are interested in the concept of Patient
Centricity specifically within clinical research. We identified three major aspects in clinical
research to promote a more patient-centric approach:

1) Patient engagement and retention in clinical research to find measures to better

engage patients during the conduct of clinical trials and to insure patient retention
throughout the study.

2) Improving data collection methods and data quality in clinical research taking
advantage of technological progress and advances to improve data collection
methods and data analysis, to therefore lead to higher data quality and more robust
and relevant clinical evidence.

3) Strengthening the human aspect in clinical research - patients are human beings and
not merely research subjects hence, a greater consideration to the human aspect in
the design of clinical trials is needed.

Several recent initiatives in the pharmaceutical industry have been initiated to promote Patient
Centricity, as Listening to the patients voice for feedback during the design of clinical trial
protocols, or giving patients a lay summary of trial results at the end of the study (21).

Another approach to drive Patient Centricity in clinical research is the use of emerging
technologies in smart devices, social networks and other innovations to facilitate the concept
of Remote Clinical Trials (also called digital clinical trials, mobile clinical trials or virtual
clinical trials). This research paper focuses mainly on this question: How to strengthen a
patient-centric clinical research culture in the pharmaceutical industry through the
development of a remote clinical trial model in clinical research? The aim of our work is to
11
build a remote clinical trial model by using modern components to enhance various aspects of
clinical research and promote the concept of Patient Centricity.

This exploration is motivated by a genuine desire to constantly improve the added

value provided by clinical research towards patients, but also by a clear strategic mandate
from the pharmaceutical industry to head towards patient centricity. Our work is sponsored by
the pharmaceutical company Boehringer Ingelheim (BI), demonstrating a sincere desire for
cultural change towards a more patient-centric approach in all its activities.

Methodology

Review of the public literature in reputable journals and important policies of

regulatory agencies in North America to establish the foundations for success of the
Remote Clinical Trial model in clinical research.

Review of the current technology (and new technology projects) in the field of
pharmaceutical innovation and their potential impact on the realization of the Remote
Clinical Trial model concept in clinical research.

Interview(s) with Key Opinion Leaders (KOL) in the pharmaceutical industry,

healthcare (primary care phyisicans (PCP), principal investigators, clinical research
coordinators) and/or regulatory agencies (FDA, Health Canada), to obtain a better idea
on the industrys capacity to accept this new concept and to lead it to implementation.

Search for a remote clinical research model by addressing the following aspects:

o Patient recruitment and retention in clinical research

o Informed consent

o Data capture and endpoints measurement

o Clinical research monitoring and treatment adherence

o Patient engagement in clinical research

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 o Practical, clinical, technological, ethical, regulatory, legal and economic
considerations with regards to the Remote Clinical Trial model in clinical
research

o Improving data quality in clinical research with real-world data collection,

where patients are not necessarily in an artificial clinical setting, but instead
in a real-world daily life setting.

Anticipated Results

Proposal of a model (completely remote or hybrid) for clinical research

Application of the proposed model in a real phase II (safety) clinical trial, phase III
(efficacy) or phase IV (post-marketing), by providing a synopsis of a clinical trial
protocol based on the Remote Clinical Trial model.

Proposed changes to the regulatory and legal policies necessary for the applicability of
the proposed Remote Clinical Trial model, both federal (Health Canada / FDA) or
provincial / state (Canada / US).

13
 3. Remote Clinical Trials a model for the industry
The development of a traditional clinical trial requires several preliminary steps. It
goes without saying that drug discovery and preclinical research are two critical stages in the
development of a new drug entity. Subsequently, during the clinical period (phases I, II and
III), the investigational new drug passes through several stages with many different teams
which will conduct a properly planned clinical program in order to bring it towards approval
with regulatory agencies. For each clinical trial, the plan starts by drafting the clinical protocol
that determines the parameters of the study, the patient recruitment strategy, conduct and
monitoring of the study during its course, data collection and analysis and finally the
preparation of the regulatory dossier. Each of these steps is typically conducted by one or
more teams working together to complete the clinical study successfully. The traditional
clinical trial is typically centered on clinical sites that treat patients for the given indication,
and all the steps mentioned above involve the commitment, support and contribution of the
staff at clinical sites.

The preliminary steps necessary for developing a remote clinical trial are virtually the
same as a traditional clinical trial. What differs between the two is the implementation strategy
employed at each step. With the concept of Patient Centricity, the pharmaceutical industry can
take advantage of various opportunities available to change the clinical operations culture
around the conduct of clinical trials.

By its simplest definition, a remote clinical trial is a clinical trial eliminating or

significantly reducing the contribution of clinical sites, keeping one central coordinating site
for the study, generally one to which the principal investigator is affiliated. Therefore, the
remote clinical trial is completely centered around a single clinical site and around the patients
participating in the study, and not around multiple sites as is the case traditionally. This
divergence of the focal point in the development of clinical trials is a major change in the
clinical research conduct paradigm, and introduces a fresh outlook on each step mentioned
above. To better realize this concept, it is important to define a model of remote clinical trial
conduct for the pharmaceutical industry, exploring the different opportunities available at each
stage of trial conduct. Also, it is important to consider the ethical and regulatory environments

14
governing the development of a remote study, ensuring that the remote nature of the trial does
not compromise the quality, acceptability and relevance of the evidence generated by the
study.

3.1 Ethical and Regulatory contexts for the Remote Clinical

Trial

3.1.1 Ethical context: ICH E6 and ICH E8

The ICH guidelines (International Conference on Harmonization of Technical

Requirements for Registration of Pharmaceuticals for Human Use) form the base onto which
the pharmaceutical industry refers to during the research, development and registration of
pharmaceutical products. Clinical research conducted by the pharmaceutical industry must
generally comply with ICH guidelines. These are classified into 4 classes, each with several
guides: Quality (ICH Q), Security (ICH S), Efficacy (ICH E) and Multidisciplinary (ICH M).
The conduct of clinical trials is especially affected by ICH E. For the development and
implementation of a remote clinical trial, it is especially important to know the basics of ICH
E6 guidelines (Good Clinical Practices) and ICH E8 (General Considerations for Clinical
Trials) and ensure compliance with these guidelines (22, 65).

Among the principles outlined in ICH E6 (22), it is especially important to ensure that
the remote clinical trial does not compromise the rights, protection and well-being of patients
enrolled in the study. Additionally, patient data privacy and confidentiality must be attested
and the trial must conform to the declaration of Helsinki (66). It is also essential to obtain
proper informed consent from each patient prior to their participation in the study to ensure
that the patient has at his disposal all the necessary information, despite the absence of a
clinical site for the study. It is important to note that the lack of clinical sites participating in
the study does not amount to eliminating the presence of a principal investigator, competent
clinical staff and the contribution of an ethics committee affiliated with the study. On the
contrary, according to the principles of good clinical practices (GCP) (22), these
responsibilities are transferred to the central coordinating clinical site which is affiliated with

15
the principal investigator, clinical staff and the ethics committee / IRB. The central
coordinating site becomes therefore a mega clinical site and the only one with which patients
interact. The central coordinating clinical research sites responsibilities will be reviewed in
more detail in the following pages. Moreover, in the context of a remote clinical trial, the
collection, management and storage of data must conform to the principles of ICH E6, while
ensuring data privacy and patient safety. Finally, adequate monitoring should be in place
despite the absence of clinical sites to ensure data quality and patients well-being during the
course of the study (22).

3.1.2 Regulatory context FDA

The FDA is often the most courted regulatory agency of the pharmaceutical industry.
Indeed, with respect to innovation in clinical research, pharmaceutical companies mainly seek
the FDAs influence and support from a regulatory perspective. This attitude therefore forces
the agency to be more proactive in the discussion of innovation, and thus gives it a leap over
other global regulatory agencies in that regard.

First, all the principles of ICH guidelines discussed earlier also apply to the FDA,
which clearly adheres to them according to its Code of Federal Regulations (CFR) (67). Every
clinical trial that is conducted in the United States or that is part of the regulatory dossier for
the commercialization of a pharmaceutical product must absolutely adhere to Good Clinical
Practices (GCP) detailed in the ICH guidelines (22), and comply with all ethical
considerations described above.

In addition, the FDA continues to take a leading position with respect to certain
innovations having the potential to revolutionize clinical trial conduct and execution. The
agencys recent publications are a witness to this affirmation, as they attempt to address
modern themes affecting clinical trials; including risk based monitoring, electronic informed
consent, electronic source data and mobile medical applications (23, 24, 25, 63).

In 2013, the FDA published recommendations for Risk-Based Monitoring (RBM) in

clinical trial conduct, which describes the position of the agency and its recommendations for
central monitoring of clinical trials (23). In this document, the FDA recognizes that there are
several methods for the monitoring of clinical data, like centralized monitoring and on-site

16
monitoring. The agency considers it acceptable and even preferable to use a centralized
monitoring method (based on the establishment of key risk indicators for each study and the
monitoring of these risks facilitated by technology), and that this practice is consistent with
ICH E6 guidelines. The FDA also states that the clinical trial sponsor must strategically use
various available monitoring methods in order to develop a risk-based monitoring plan
(RBM). We consider therefore that Risk Based Monitoring is a necessary component for the
development of a remote clinical trial, and the FDA lays an adequate framework for its
implementation with their recommendations.

Also in 2013, the FDA published another document of recommendations detailing its
position on the electronic source data (eSource) (63). In it, the FDA describes the basics of
electronic data capture at the source, including the description of data originators (clinical
investigator, patient, medical device, electronic health record, automated laboratory system or
other technologies) and electronic data entry at the source, directly in the case report form
(eCRF). The agency recommends confirming that all data originators be properly documented,
and any data input by any data originator must be attributable to him. It also describes the
various electronic sources for data capture. Also, any data element entered in the eCRF must
be assigned to a study subject and must record the exact time of the data entry. Data validation
is highly recommended in the guidance document, to avoid data capture errors, and any
necessary changes should only be made by the principal investigator or a delegated clinical
study staff. Finally, the principal investigator shall review the eCRF data and electronically
sign them prior to any submission to the FDA, in compliance with 21 CFR - Part 11 ruling.

Another recent paper by the FDA describes the position of the agency regarding
mobile medical applications (24). A mobile medical application is defined as any software
application running on a mobile platform (i.e. smartphone) or on the web, for use as an
accessory to a regulated medical device or to transform a mobile platform into a regulated
medical device. Given the increasing proliferation of mobile platforms and applications in
recent years, the FDA does not undertake to want to regulate any mobile application that
touches the medical field. However, it is committed to focus on any mobile application that is
classified as a medical device or accessory to a medical device. An example is the integration
of a blood glucose reader to a smartphone, therefore transforming the smartphone into a

17
glucometer. In addition, the agency is particularly looking for applications that, when
malfunctioning, can pose a risk to the safety and wellbeing of patients. This implies that the
need to validate a medical mobile application with a reduced risk may be left to the discretion
of the agency. The agencys position is very important to consider in the context of a remote
clinical trial project, because it is clear that such a project could include one or more mobile
medical applications and platforms. It is therefore important to consider the recommendations
of the FDA to determine whether such a platform or application is classified as a mobile
medical application or not, and as appropriate to confirm its validation before use if necessary.

Finally, in early 2015, the FDA issued new guidance for the industry that describes its
position about an innovation that is becoming increasingly important in clinical trials:
electronic informed consent (25). It defines electronic informed consent as the use of
electronic systems that employ multimedia processes to present the necessary information to
the patient in order to obtain his informed consent to participate in a clinical trial. In their
guidance, the FDA responds to many common questions about the new technology and
emphasizes that informed consent must be regarded as a complete process to provide the
necessary information to patients and not only the obtaining of a signature for the consent.
Therefore, electronic informed consent should facilitate the adequate understanding of the
patients. Also, it is acceptable according to the agency that it takes place at the clinical study
site or can be done remotely, provided that adequate measures are taken to insure patients
understanding. The agency also described that electronic signature can be used as a
replacement for physical signature, but it is important to give a copy of the signed informed
consent document to the patient after signature. Finally, the FDA guidance describes that the
electronic informed consent process must ensure confidentiality of patient data and the
information on the electronic system must be properly encrypted. It explains that the role of
the ethics committee remains unchanged for electronic informed consent, and that the
protection and welfare of patients remain the priority in clinical trial conduct and execution.
Hence, the recommendations in this guidance document from the FDA are also important to
consider in our model because it is conceivable that a remote clinical trial would use electronic
informed consent technology when initiating patients to the study.

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 3.1.3 Regulatory context Health Canada

Given that Canada is a much smaller market than the United States, it is
understandable that the Canadian regulatory agency, Health Canada (HC), does not take a
leading position like the FDA on innovation in clinical research. However, it is relevant in the
context of this work to explore HCs regulatory framework for it may affect the feasibility of a
remote clinical trial in Canada.

First, just like the FDA, all the principles detailed in the ICH guidelines also apply to
HC. Any clinical trial taking place in Canada or which is part of a submission for marketing
approval of a pharmaceutical product must absolutely comply with Good Clinical Practices
(GCP) detailed in the ICH guidelines, and comply with all ethical considerations described
earlier.

In addition to GCPs, it is also important to know the position of the Canadian agency
with respect to medical devices. HC classifies medical devices into four different classes,
depending on the degree of risk they carry to patients. Class II, Class III and Class IV medical
devices require a license before being marketed and sold in Canada (26). While HC has no
specific guidelines for mobile medical applications, the regulations of the agency for medical
devices can be extrapolated to predict its position on mobile medical applications. According
to the Food and Drugs Act published on the Ministry of Justice of Canadas website, a medical
device is defined as "any instrument, apparatus, contrivance or other similar article, or an in
vitro reagent, including a component, part or accessory of any of them, that is manufactured,
sold or represented for use in the diagnosis, treatment, mitigation or prevention of a disease,
disorder or abnormal physical state or its symptoms, in human beings or animals" (27). This
demonstrates that the intended use of a mobile medical application proves to be one of the
determining factors from a regulatory perspective. In the context of a clinical trial, if the use of
a mobile medical application is intended to diagnose, measure symptoms, cure or prevent any
disease, it should be regulated as a medical device for HC. As described above, medical
devices are classified by HC according to the risk they pose to patients and therefore
manufacturers of mobile medical applications with the intent to use them as medical devices
as defined by the Food and Drugs Act are expected to validate and classify them with HC.
This is very relevant for the design and conduct of a remote clinical trial in Canada because it
19
is important that any mobile medical application that qualifies as a medical device and is used
as part of a remote trial gets properly classified and validated with HC.

Regarding the use of electronic informed consent, HC does not yet have a clear
position. The Office of the Privacy Commissioner of Canada published in 2014 a guidelines
document to address the issue of consent requirements under private sector privacy laws, in
order to ensure proper consent is obtained by any organization that interacts with private
consumer data from Canadian consumers through the Internet and to ensure consumer data
privacy (28). It is possible to draw some parallels between these guidelines and the process of
electronic informed consent for a clinical trial in Canada, such as obtaining consent before
using consumer private data, the need to clarify to consumers how their data will be used and
to ensure data privacy. However, in the absence of the clinical research context, such
extrapolations are limited, and HCs position on electronic informed consent cannot simply be
assumed to be similar to the Office of the Privacy Commissioners guidelines.

Having said that, it is important to generally note that the use of any electronic solution
in a clinical trial, be it a mobile application, electronic informed consent, or a medical device
connected to a smartphone must meet the general requirements of regulatory agencies. Thus, if
such a solution is validated and deemed acceptable for clinical research use for the FDA, it is
acceptable to assume that HC will generally have a similar position to its American
counterpart.

3.2 Components of the Remote Clinical Trial model

As described earlier, a remote clinical trial is a clinical trial that significantly reduces
or eliminates the contribution of clinical research sites, keeping only one central coordinator
site for the study, generally one to which the principal investigator is affiliated. It is also a
clinical trial that takes advantage of mobile and digital health technology to make its
implementation more effective.

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 3.2.1 Patient Recruitment and Retention in clinical research

Like any clinical trial, the remote clinical trial starts with patient recruitment, which is
generally recognized as a limiting step in clinical trial conduct. Indeed, one of the most
common problems faced by several clinical trial managers is a slower and more difficult than
anticipated patient recruitment, which usually results in an extension of the trial timelines or
its completion with a smaller number of patients than expected (29). In addition, it is estimated
that on average over 30% of enrolled patients in a clinical study leave the study prematurely,
resulting in less data available for the analysis of study results (30). Therefore, it is clear that a
proper patient recruitment and retention strategy is necessary to keep patients engaged in the
study towards its success.

Traditionally, patient recruitment is done through physicians referrals across

healthcare institutions or day clinics, or through advertisements aired through traditional
media outlets like television, radio or newspapers. These strategies, that may seem suitable at
face value, do not deliver the desired results in many cases. The increasing demand for
research subjects resulting from the increased number of clinical studies over the past decade
makes it more difficult to recruit patients for clinical research. Additionally, the necessity to
have treatment-naive subjects in some cases further reduces the pool of available patients for
clinical research. According to a report from Tufts University in Boston, 89% of clinical trials
are generally able to recruit the necessary number of patients, but not without almost doubling
the duration of the study to achieve this goal (31). Also according to the report, nearly half of
clinical sites involved in clinical trials recruit fewer patients than expected, or even worse, fail
to recruit any patient at all. These challenges demonstrate the urgency for the industry to seek
new alternatives to refine patient recruitment, in the hopes to reduce the costs and duration of
clinical research.

The ubiquity of the Internet and its impact on healthcare and clinical research domains
has led some to formulate the term "rise of the e-patient", which serves as a witness to this
phenomenon and to the opportunity it brings. According to a survey from the Pew Research
Center conducted in 2014, 72% of US Internet users say they use the internet to search for
health related information (13, 14). This proportion rises to 85% for European internet users
who say that they turn to the internet to obtain information on their health and on their
21
pharmaceutical prescriptions (15). Moreover, the recent proliferation of social networks
presents an opportunity for consumers to come together around issues of common interest to
engage in discussions and share all kinds of information. Meanwhile, several communities of
patients with common medical conditions come together through dedicated social networks
and share information about the experience of living with their condition. These social
networks are proving to be a golden opportunity for clinical research as it becomes possible to
conduct a recruitment campaign for clinical research, specifically targeted to patients with a
particular disease. Some examples of these dedicated social networks are PatientsLikeMe
(32) MyHealthTeams (33) and SmartPatients (68). PatientsLikeMe allows patients
around the globe to come together and share information about their illnesses, including their
laboratory findings and their daily symptoms. On their website they claim to represent more
than 2500 conditions regrouping more than 380,000 patients (32). MyHealthTeams is a
platform for patients with chronic diseases to come together and share information about their
experiences of living with their disease. This platform differs from PatientsLikeMe in that it
specializes in chronic diseases and provides specific social networks for each of the 15 chronic
diseases it supports so far (33). The third platform mentioned above, SmartPatients, is
similar to the previous two, but is not limited to chronic conditions, seeming to rather have an
emphasis on oncology. This platform not only allows patients to learn from their peers on the
condition that commonly affects them, but also gives them the opportunity to seek treatment
or clinical trials for which they may be eligible.

The spread of dedicated patient social networks are not limited to those mentioned
above; several others exist or will take shape in the coming years. A clear benefit of the
opportunity they present is that patients feel empowered to control or improve their condition
when they have more information about their symptoms, combined with the support from the
community of patients sharing the same condition. Also, the potential partnership between
these networks and the pharmaceutical industry can result in a more focused patient
recruitment strategy since patients are already grouped by condition. This can become even
more interesting for orphan diseases, where the number of patients is already scarce. Finally, a
potential partnership with healthcare professionals would give more credibility to these
dedicated social networks by allowing the disclosure of accurate information about the

22
conditions affecting patients that are in those communities. Thus, the proper collaboration
between the different stakeholders involved in the patients health can derive a greater
engagement for the treatment of their condition, and can lead to better results for patient
retention during clinical research.

Electronic health records (EHR) are becoming increasingly important in the healthcare
domain in Canada and the US, in part because of recent legislation in both countries. EHRs
collect all patient health data from different institutions in order to have the correct up-to-date
health information for each patient. They enable healthcare professionals to make better
decisions about the health of their patients, and thus potentially reduce health-related risks to
patients. In Canada, the federal and provincial governments took the initiative to change their
data collection procedures towards an electronic patient health record system (34). In the US,
the payer being mainly the private sector, patient EHR data collection is done at the level of
private insurance companies. The HITECH legislation (Health Information Technology for
Economic and Clinical Health Act) passed in the United States in 2009 promotes the use of
electronic health records across all health clinics, encouraging data sharing across different
healthcare providers. The standardization of data collection at the EHR level is proving to be a
clear opportunity for targeted patient recruitment in clinical research.

The company Optum, affiliated with the medical insurance giant United Health Group
in the United States, seized this opportunity by offering data intelligence services to the
pharmaceutical industry enabling them to plan their recruitment strategy with their broad base
of insured patient data (35). Using the Clinformatics platform provided by Optum, a clinical
research sponsor can locate patients by specific conditions or symptoms and thus obtain
information on the feasibility of a study based on the number of eligible potential patients in a
geographic location for the study of interest. Using the results of this tool, sponsors can work
with primary care physicians to determine eligibility of their patients in the clinical study of
interest. This tool represents only a small opening to the use of insured patient data, as it
doesnt provide the possibility to identify patients, and therefore does not allow direct
recruitment of patients from the database. However, it is not inconceivable that other medical
insurance providers or other electronic health records providers in Canada or the United States
also take this opportunity by implementing patient recruitment services for clinical research.

23
Indeed, if it becomes possible to maintain patient confidentiality and respect for their dignity
and generate an IT platform based on insured patient data, this could become an excellent
opportunity for targeted patient recruitment. Such a platform could obtain the consent of the
insured persons to be contacted or not for clinical research if they are eligible, and generate a
viable set of patients that can participate in clinical research. Anolinx, a provider of IT
services in clinical research for the pharmaceutical industry, recently conducted a proof-of-
concept pilot study with patient recruitment assisted by electronic health records. Their pilot
project demonstrated that this new concept is almost 2.5 times more effective than traditional
methods of recruiting patients (36). It is therefore plausible that this idea would be expanded
in the coming years, and could be a prime asset for the conduct of a remote clinical trial.

Finally, referrals from primary care physicians continue to be an effective strategy to

recruit patients for clinical research nowadays. However, a major obstacle to this strategy
remains that most doctors and patients do not have access to this information easily. The
ClinicalTrials.gov website (69) contains a wealth of information about clinical trials
worldwide, but this information is not very easy to read and navigate for patients and
caregivers to find the studies to which they are eligible. It is therefore useful for patients to
view this information on clinical trials globally, to enable them and their physicians to easily
determine eligibility for participation in a particular clinical trial. The platform TrialReach
(70) specifically provides liaison services between patients and clinical studies based on
eligibility criteria. In fact, the platform mines the ClinicalTrials.gov data and applies
algorithms to simplify the language of study synopses. In addition, the algorithm passes
patients through a short questionnaire to determine their eligibility before referring them to the
studies in which they can potentially participate. This makes the screening for suitable clinical
studies much easier for patients, and therefore supports targeted patient recruitment and
increased participation in clinical research. Similarly, the platform puts interested patients in
contact with the medical team that supports the trial, thus promoting faster access to
information. Another mobile platform, CAVII (71), is a mobile application that allows
patients to combine their electronic health records and other information about their lifestyle
and health status, and offers them participation in clinical trials based on their data.

24
 Regardless of which mobile platform is used, the idea to facilitate matching of patients
to clinical studies through mobile applications and smart algorithms has an increased potential
to improve patient recruitment for clinical research. The awareness and proliferation of this
technology among physicians are necessary for the success of initiatives similar to
TrialReach and CAVII. However, physicians have no clear motive or incentive for
referring patients to clinical studies outside their practice, which may possibly decrease the
number of patients they follow and have a negative impact on their revenue. Therefore, it is
important to address this paradox, which can become an obstacle to the use of this concept for
a remote clinical trial. One strategy would be to extend the role of General Practitioners (GP)
and consider the discussion of participation in clinical studies with patients as a paid medical
act. However, this will require major changes in legislation and in the modalities of
remunerating doctors in healthcare. Such changes would not necessarily be trivial to make,
while many obstacles are anticipated before they can potentially be adopted by healthcare
payers (government or private insurance). Another strategy might be to allow GPs and clinics
to perform the necessary tests (such as blood draws, electrocardiogram, etc...) before the study
to determine the eligibility of patients, and throughout the duration of the study. This would
place an additional source of income for the clinic without adding the necessary overhead for
clinicians to become principal investigators in a study. Moreover, the establishment of a new
form of strategic partnership between clinical trial sponsors and such clinics may be required
for proper remuneration of GPs involved. Platforms cited earlier such as TrialReach and
CAVII are currently mainly based in the US and their potential utility to recruit patients in
Canada and Europe remains therefore limited at this time. Nevertheless, their expansion into
these regions of the world can certainly be anticipated in the future, especially if their
effectiveness in recruiting patients is demonstrated in the long term.

In short, the components of patient recruitment mentioned above are essential to

running a remote clinical trial. Consequently, it is necessary to have a recruitment strategy
operating these components to ensure the success of the remote clinical trial concept.

25
 3.2.1.1 Patient Recruitment and Retention Strategy for the Remote Clinical Trial

In the digital world era, it is essential that any large clinical trial, including remote
trials, have a dedicated website with all information related to its implementation. This
website thus becomes the ultimate web presence for the trial, and is therefore visited by all
who are interested or curious about the study. It should serve as a comprehensive information
portal and use various multimedia techniques to capture the interest, engage and educate key
stakeholders for the trial. With that, it becomes extremely important to employ appropriate
search engine optimization techniques in the strategy to get the most possible traffic to the
study website. Thus, study sponsors should be able to benefit from the many avenues of
Internet advertising, such as targeted ads on Google, Facebook, Instagram, Pinterest
and other social networks, to maximize traffic to the study website for targeted audiences.
Moreover, depending on the therapeutic area of the study, sponsors must establish partnerships
with specialized social networks for the condition in question, such as those described earlier
(MyHealthTeams, SmartPatients, PatientsLikeMe and others). These dedicated social
networks allow direct recruitment of targeted patients, through pre-screening surveys
determining the eligibility of the referred patient. Added to this is the interaction with referring
physicians and partnering with platforms such as TrialReach to promote the study and allow
the transmission of correct information to patients and their physicians. The expansion and
accessibility of these platforms to referring physicians is required for their success, which is
not yet fully accomplished today. Finally, the remote clinical trial may greatly benefit from a
recruitment based on electronic health records as well as health insurance databases. Although
access to these platforms for direct patient recruitment is not fully established at this time, it is
clear that they have a place of choice for enrolling patients in a remote clinical trial in the
future, since they allow the targeting of specific patients with a condition of interest in
research. It is conceivable that an increase in the number of implementations of remote clinical
trials in the future can promote the rise and effectiveness of these platforms and improve
patient recruitment methods for clinical research globally.

After patients get enrolled in the remote clinical trial, it is necessary to have a patient
engagement strategy to keep patients involved in the study and thus to retain them throughout
the duration of the trial. Patient engagement and retention in a clinical study can be established

26
through constant communication facilitated by modern technologies such as mobile
messaging. This would help educate patients on the study treatment and provide them
reminders of the various study milestones. Patient engagement can also be improved through a
customized mobile application hosting a patient portal containing all relevant study
information. A well-educated patient about the study, informed about treatment details and
potential risks and benefits, is usually a better engaged patient. The patient engagement and
retention strategy is not limited to the utilization of mobile technology, but also depends on the
degree of patient satisfaction for the study, and the disruption to daily life that participation in
the study brings to the patient. Thus, study design has a definite impact on patient engagement
and retention in the study. Adopting a less disruptive study design for the patient, in terms of
data collection and the number of visits, while ensuring that the patient remains well informed
about the study, can be very promising in this regard. The following sections present a
comprehensive strategy for patient engagement and retention in clinical research, starting with
electronic informed consent, electronic data collection and remote monitoring.

3.2.2 Electronic Informed Consent (eConsent)

According to the ICH E6 guidelines for clinical research, any patient must give
voluntary informed consent before participating in a clinical trial (22). The consent form must
describe all relevant information to the patient's participation in the study, including treatment
procedures, details of the clinical protocol and the patient's compensation for participating in
the trial. The patient should take the necessary time to read and understand the details of the
form, ask any questions related to his participation and obtain answers, and eventually sign
and date the form, which must be countersigned by the principal investigator and in some
cases also by an impartial witness, if the subject of the study is unable to read. It is important
to note that informed consent is not only obtaining the signature of a patient on the form for
participation in the study, but rather an integral process for the patient to have all the necessary
information to make an informed decision to join the study.

27
 Traditionally, the informed consent process in clinical research is based on a paper
form describing the necessary information on the clinical study protocol. Sometimes the
patient must read, understand and sign several documents to provide consent for participation
in the study. These documents are generally long and full of scientific jargon despite the need
to present the information in a fairly simple vocabulary to be understood by patients. Despite
their widespread use in clinical research, these methods of obtaining informed consent are not
always adequate for generating a true consent from the patient. First, it is not easy to really
determine whether the patient truly understands the various aspects of the study to which he
agrees to participate. Yet the ICH E6 directive describes that the investigator and clinical staff
must take the time to answer any questions the patient has about the study, which promotes a
better understanding for the patient. However, the reading of a long document containing
unfamiliar scientific terms adds a barrier to understanding for patients. This is particularly
more pronounced for illiterate patients or those with a minimal level of education (37). In
addition, the management of the informed consent process and the need to re-obtain consent in
an amendment to the study protocol poses an additional risk of non-compliance with
regulatory requirements, especially when clinical staff does not immediately recognize the
need to inform the patient of the amendment. Finally, having multiple versions of the consent
form through the duration of the study raises the risk of incorrectly consenting patients with
older versions of the document, resulting yet again in non-compliance with regulatory
guidelines.

It is obvious that some of these difficulties can be resolved by continuous improvement

of clinical trial conduct procedures done by the clinical study staff. Nevertheless, technology
can greatly contribute to these improvement efforts through the usage of electronic informed
consent (e-Consent). This technology was first introduced in 2012, in the context of Pfizers
REMOTE study (64). Since then, several clinical research sponsors have adopted e-Consent
for some of their studies. Electronic informed consent involves the use of multimedia via an
electronic device (desktop, laptop, tablet or smartphone) to present the complete information
about the clinical trial and obtain informed consent prior to patient enrollment in the study.
Generally, a short video is first presented to the patient, describing clinical research in general
and the details related to participation in the clinical study of interest. Next, the informed

28
consent text with specific details of the study is presented to the patient, generally in the form
of a document on the device, but sometimes through the use of multimedia. The patient can
put his initials on each page confirming his understanding, and even highlight unfamiliar terms
or sections in a particular paragraph. Also, patients can get definitions of these unfamiliar
terms immediately during the e-Consent process. It is important to clarify that electronic
informed consent is not expected to eliminate the patient-investigator interaction when
obtaining consent, but rather supports better interaction between them. Before signing the
electronic document, the principal investigator or the clinical study coordinator must take the
time to answer all the patients questions. Also, it is possible to apply a knowledge review
survey to the patient at the end of the process, to verify proper understanding of all the
sections of the study to which he agrees to participate. The purpose of this knowledge review
is not to refuse participation for patients who do not understand the study completely, but
rather to serve as a reference point for clinical staff and sponsors as to which concepts of the
study are more complex for the patient. This can then serve to train clinical staff to spend more
time to revisit these concepts with patients before signing the document. Also, it is possible to
gather metrics about time spent on each page or section of the document to confirm that the
patient has really taken the time to read the document. Finally, the signature can be done
electronically, in compliance to the FDAs (21 CFR - Part 11) ruling (72) or on the printed
paper version at the end of the process. The patient may also decide to review the document
from the comfort of his home through a web portal and consult with family members before
providing their consent to join the study. The signature of the document must be in the
presence of the investigator, and in some cases also of an impartial witness, as per ICH E6
guidelines (22).

In an article published in 2013 in the journal PLoS ONE, Rowbotham et al.

demonstrated the superiority of electronic informed consent relative to paper informed consent
(38). The article describes the randomization of subjects to undergo the informed consent
process electronically or paper-based, followed by a knowledge-review quiz to determine the
level of understanding of the subjects for the study based on the informed consent method
utilized. The results showed that on average, patients who received the electronic informed
consent have a better score than those receiving the paper version (75% against 58%). Also,

29
subjects with the electronic consent were more engaged in the process, spending more time
with the consent document on average (22.7 minutes against 13.2 minutes) and also asking
more questions (5.7 against 4.2 questions). It is therefore clear that patients better receive the
necessary information with electronic informed consent, with a better overall understanding
and longer retention of that information. Also, a better informed patient is generally a patient
that is more engaged, which should lead to better patient retention in the study. Document
management in the e-Consent platform allows to always obtaining consent with the latest
version. Subsequently, the electronic informed consent provides better compliance with ICH
guidelines and regulatory agencies requirements. The potential integration of the electronic
informed consent system with the patients electronic medical record could also facilitate the
identification of specific patients that need to re-consent in case of an amendment (e.g. all
male patients aged between 45 and 55 having a systolic pressure of 160 mmHg). The
electronic informed consent system allows role-based access, thus limiting access to private
patient health data only to the principal investigator and the qualified study personnel.
Sponsors can also access the system, without the ability to see patient identifiable data.
Finally, in a world which tends more and more towards a paperless culture, electronic
informed consent is a technology that allows clinical staff to access all consents of all patients
digitally, without having to sort through a multitude of paper files. However, there are some
challenges that arise with the use of electronic informed consent, such as costs associated with
the implementation of this technology, as well as wireless connectivity required at the clinical
site.

In the absence of clinical sites for the implementation of a remote trial, it is clear that
electronic informed consent becomes an indispensable asset for the study. However, since it
implies that consent is done remotely, some logistical challenges and obstacles can be
foreseen. First, it is important to verify and validate the identity of patients who provide their
consent remotely, to confirm that the patient is really the person who they claim to be. Also,
electronic informed consent obtained remotely eliminates the ability to consent illiterate
patients or patients having a disability that prevents them to read. Moreover, it is important to
have a qualified clinical staff member that can respond to patients questions immediately
when necessary, before obtaining consent for the study. Thus, the patient can pass the initial

30
screening stage to determine their eligibility to the trial by answering questions about
eligibility, pass through identity validation, and then immediately begin the electronic
informed consent process. Once this process is complete, the patient should be placed in direct
contact (by phone or audiovisual conference call) with the principal investigator or qualified
clinical study personnel to have answers to all their questions and then complete the signing
and co-signing of the document. Informed consent cannot be considered complete without the
necessary interaction between the patient and clinical staff, and without the signature and co-
signature of the final document. Finally, like any form of digital communication done on the
internet, it is important to perform data encryption and ensure patient data privacy throughout
the consent process. This can be accomplished through the use of proven encryption methods
in the e-Consent application, which is typically ensured by the e-Consent application vendor.

Alternatively, the informed consent process may be performed from the patient's home
on an agreed date after the initial screening. This implies having the direct presence at the
patient's home of a clinical staff member, a clinician affiliated with the principal investigator
or a registered nurse, which would allow direct contact between the patient and a qualified
person during the process. It does not however take away the need to have contact with the
principal investigator facilitated by clinical staff from the patients home during the process,
through an audiovisual call.

The financial consideration of implementing e-Consent can be also seen as an obstacle,

because there is an added cost compared to paper informed consent. However, it is anticipated
that in the long run, the electronic informed consent technology becomes less expensive, and
the cost-benefit ratio becomes more favorable. Also, the utilization of this technology on more
trials from the sponsors clinical research portfolio may also improve the cost-benefit ratio.
Hence, it is important for the pharmaceutical industry to begin gradually adapting their
processes for the use of this technology despite the added costs in order to benefit from the
improvements it brings long term.

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 3.2.3 Electronic Data Capture (eSource, ePROs, Wearables)

Clinical data capture is an important element for the successful implementation of any
clinical trial. For each clinical trial, it is important to have a clear data collection and outcomes
measurement strategy. The therapeutic area and the treated disease in the trial are two factors
that greatly influence this strategy. Some trials measure the improvement in quality of life
through validated questionnaires that are filled by patients at several intervals of the trial,
while others are designed to measure the patient's biometric data, such as blood pressure,
blood glucose level (HbA1C) or pulmonary function tests (FEV1/FVC) among others. It is
therefore clear that some outcomes measurements are subjective to the patient's perception in
relation to the progression of his disease with the treatment received. Others are more
objective, measuring the biological response of the body against the treatment. The decision to
use one or the other outcomes measurement for a trial largely depends on the purpose of the
study and the evidence targeted for the study. Additionally, the clinical data strategy requires a
decision to designate certain outcomes as primary in the study, and others as secondary
outcomes supporting the primary evidence generated by the study. To preserve the integrity of
results generated by a study, it is essential to have adequate data capturing methods which
would help minimize the risks of transmission and transcription errors. However, clinical data
capture today is still largely deficient compared to the digital world era in which we live in.
Indeed, most of the data for clinical trials are collected on paper case report forms (CRF),
which are usually subsequently transcribed into an electronic patient record. These paper
forms are the basis for data collection for the study, and are considered to be the primary
source of clinical data. Still, due to the manual nature of the data collection and transcription
of data from paper to electronic format, this process is highly error-prone, and can
compromise the integrity of the evidence generated by the study. To mitigate this situation,
clinical research sponsors often hire clinical monitors to validate data integrity, through a
comprehensive verification process of all source data, called Source Data Verification (SDV),
in which monitors mainly compare the paper and electronic formats to find transcription errors
and ensure data validity. This process is sometimes long and arduous, especially for a large
multicenter study. Thus, it is justified to try to improve clinical research data collection using
technology to improve the efficiency of monitoring processes and enhance data integrity.

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 3.2.3.1 eSource Electronic Data Capture at the source

With the increasing spread of electronic and computer systems, it is conceivable that
clinical research data can now be captured electronically at the source. Electronic source data
eliminate the need to transcribe data from paper forms to an electronic system, since the data
is already in electronic form at the source. This data may be reported by clinical staff during a
scheduled protocol visit or by the patients themselves via an electronic device.

For data reported by clinical staff, there are systems to capture source data on a tablet
device which hosts the case report forms electronically (eCRF) (73). The tablet thus becomes
the medium containing all source data and acts as the gateway to all data stored directly in the
clinical database on the cloud, hence avoiding the need for later transcription from paper with
all the potential errors associated therewith. Electronic data capture at the source allows for
better data quality and provides faster access to the data for the monitoring team, which can
therefore verify data integrity much earlier during the study. Also, it changes the clinical
monitoring paradigm of comprehensive SDV, since data is validated at the source through a
proper eCRF design and remain unchanged in the clinical database. Clinical data monitors can
rather review contextual clinical data, not related to the study protocol, such as the date of data
entry, for example, to contextualize the capture of these data. This non-clinical data (such as
date of data entry) can support monitoring efforts as evidence of compliance with GCP
guidelines and Standard Operating Procedures (SOPs), as well as provide evidence for clinical
protocol compliance. The clinical monitoring paradigm therefore shifts to a different level,
focusing on protocol and SOPs compliance, rather than a focus on data transcription review.
This shift is not easily achievable with the current paper data collection methods.

3.2.3.2 Patient-Reported Outcomes

Similarily, Patient-Reported Outcomes (PRO) can also be captured electronically at the

source (ePRO). As previously described, this data serves to capture the patients perception of
the progress of his/her condition, and generally consist in validated questionnaires to
determine quality of life measurements. Traditionally, these questionnaires are provided to
patients in paper form, with the intention that they fill them at several intervals during the
study to evaluate the effect of the treatment on quality of life. It is largely recognized that

33
patients dont always comply with the study protocol instructions on the completion of these
questionnaires at the planned intervals (39), and we often witness the famous parking lot
effect, where patients fill the questionnaire in the clinic parking lot shortly before the planned
study visit as described by the clinical protocol. Nonetheless, PROs are considered an
appropriate data collection method to obtain the patient's perception of the progression of their
disease. Several studies demonstrated that ePROs represent an improvement in compliance
and data integrity over PROs, and various scientific, regulatory and practical considerations
encourage the use of electronic data reported by the patient. Among these considerations, it is
easier to check the temporality of such data collection and thus verify protocol compliance.
Also, it is possible to add pre-validation to the data entry, preventing the entry of non-valid
data, thereby greatly improving accuracy and integrity of the collected data. Moreover, alerts
and reminders in the electronic system help reminding the patient of the necessary time for
data collection, leading to more accurate and more complete data, and potentially requiring a
smaller sample size (related to a reduction in missing data points) leading therefore to a
potential cost reduction (40). Also, it has been demonstrated that ePROs are equivalent and
comparable to the printed PROs in terms of the significance of the collected data, with a clear
patient preference for the electronic version (41).

Electronic data reported by the patient, also called eDiary, was first implemented using
dedicated devices, which included the validated questionnaires and all other forms of patient
data. Thus, the device was manufactured and configured specifically for the collection of that
specific patient data for clinical research (i.e. for spirometry questionnaires), and therefore did
not have the ability to incorporate other features. This approach represented a considerable
investment for the clinical research sponsor, which must therefore lease the electronic devices
from a supplier (purchase of such devices would not be beneficial because they typically
would only be useful for one study), which thus became an important obstacle for the adoption
of this technology, especially for large multi-centric studies. Also, in the digital age where the
majority of the population owns at least one mobile device (13), this approach added the
inconvenience for patients to maintain and operate an additional device from the one or more
devices they already carry. These barriers may partially explain the manifestation of a slow
adoption of the technology among sponsors and other clinical research stakeholders.

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 To counter the high costs of implementing eDiaries, a new concept emerged, assisted
by the wide spread of smartphones with consumers. Commonly known as Bring Your Own
Device (BYOD), the concept aims to take advantage from the fact that much of the
population of the modern era owns a smartphone, tablet or laptop (13). This makes it possible
to obtain data reported by the patient through a mobile application or a web portal hosting the
validated forms and questionnaires. After the patient data entry through the mobile device,
data are uploaded to the cloud database via the internet connectivity of the device. The
application can be created and managed specifically for the clinical study in question, and can
therefore serve as a portal of communication between the clinical research team and the
patient. Therefore, it can contain alerts and reminders of activities related to the study
protocol, such as filling the questionnaire at specific intervals, or the regular administration of
the investigated drug in the study. This approach could significantly reduce the required
investment for sponsors to benefit from the advantages brought by patient reported outcomes.
It also facilitates a better transition for the newly enrolled patient in the study who only needs
to get familiar with a new application on their preferred mobile device, without the need to
operate a new device. In addition, it reduces the workload of clinical study personnel,
eliminating the need to manage and distribute dedicated devices for each patient.

3.2.3.3 Wearable Devices

Complementing patient reported outcomes and the BYOD concept, is the arrival of
wearable devices, a phenomenon with growing popularity among consumers. Equipped with
sensors that can quantify various biometric measures such as physical activity, heart rate,
blood pressure and others, wearable devices are small devices that can be manipulated by
hand, and can be worn at specific locations on the human body. Grazing the futuristic cross
between the biological and electronic world imagined by some to give birth to famous
cyborgs, these devices perfectly reflect the natural progression of technology of our era. In the
digital age, we are slowly but surely seeing the birth of a new trend at the consumer level,
commonly called the "quantified self" movement. Thriving primarily from concerns of
athletics enthusiasts to quantify their activity and their vital signs during physical activities,
the quantified self movement provides a new way to capture biometric data continuously and
in real time. In addition, the rapid development of wearable devices of second and third

35
generation leads to an imminent seamless integration with smartphone technology. The
constant data obtained from wearables are now transmitted to the consumer's smart device
through full connectivity with the device and a mobile application, which in turn transmits
data to the database through the cloud. Thus, data are entered longitudinally, which allows
analysis over a long period of time, in search of trends. Consumers finally gain a lot by
knowing their own tendencies and can therefore adjust their lifestyle according to the data,
being for example more active or deciding to change their nutrition habits for better health. It
is assumed that the use of wearable devices may encourage consumers to pay more diligent
attention to their health and change their habits towards a healthier lifestyle. However, despite
the clear potential that these devices can bring to consumers, the hypothesis supporting their
benefits to a healthier lifestyle remains unproven so far (42).

In contrast, since their appearance a few years ago and their proliferation into the
market, it is accepted that in addition to the known usefulness of wearables in the field of
sports and athletics, they present an excellent opportunity to the collection of real and
continuous data in the field of clinical research. If this opportunity materializes, it can pave the
way to a new paradigm in clinical research: the ability to collect data continuously and in real
time. The continuity and explosion of the amount of collected data that this opportunity
symbolizes can lead to more rigorous clinical evidence based on real-world data. Similar to
ePROs, wearables generate data reported by the patient, except that the data is more objective,
reflecting the true nature of biometrics rather than the patient's perception of his condition. By
their presumed objectivity, wearables data can be more reliable than ePROs for certain
conditions and can therefore serve as the basis for collecting primary or secondary endpoints
in a study. Also, the ability of wearables to seamlessly integrate with smart mobile platforms
owned by the patient gives the opportunity to be constantly connected with the study database
via the cloud, ensuring continuity and backup of clinical data in real time. The BYOD concept
perfectly fits in this model, where the patient has to simply download an application on his
own mobile device and establish connectivity with the wearable to start collecting data.

The potential of wearables in clinical research is extremely promising. For example, in

the respiratory (i.e. COPD), cardiovascular (i.e. cardiac rehab) and immunological (i.e.
rheumatoid arthritis) therapeutic areas, clinical protocols often use the 6-minute walk test in

36
the clinic as an indicator of progress of the studied condition (43). Using a wearable device
measuring the patient's physical activity, it is not inconceivable to be able to trace the patient's
walking activity during the treatment period, and assess the effect of the dose of treatment on
improving the condition. Such a measure is more accurate and provides a better indicator of
disease progression in real-time and in a real-world situation. Similarly, blood pressure, blood
glucose levels or heart rate measurements at hourly intervals, and an electrocardiogram can all
be captured using wearable devices, saved on the mobile platform and uploaded to the cloud
clinical database without additional effort required of the patient or the clinical team. The huge
potential that this concept can lead to can translate in better clinical data monitoring, improved
compliance with the protocol, and most importantly more patient-centric clinical research. The
potential of these objective measurements reported by the patient through a mobile platform
and the cloud is not limited to wearable devices, but rather open to all validated medical
devices coupled with an app on a smart device. One such example is the use of a spirometer
for assessing the patient's respiratory force with respect to a given treatment. Just like
wearable devices, the spirometer transmits data through the mobile platform app via the cloud
to the clinical database. This idea can no longer be considered the domain of the future, as
pioneers in the pharmaceutical industry are already beginning to explore opportunities brought
by wearable devices. For example, companies like Garmin and Medidata have recently
partnered to facilitate the integration of data from wearable devices that have an
accelerometer, which would assess physical activity and measure steps taken by the patients
(74). Another example of the pioneers in this field is the partnership between companies like
GSK, Medidata and VitalConnect to assess the concept of remote data collection using a
small patch that is fixed on the patient's chest, and containing a sensor measuring heartrate to
generate an electrocardiogram and seven other biometric measurements in study subjects (44).
This wearable device is approved by the FDA (510 k approval) and the data produced by it
can be used for clinical research.

This kind of innovation in clinical research made possible by smartphones, tablets and
cloud computing is not limited to wearable devices. Another application of this concept can be
done in medical devices, which are often used in clinical trials. For example, in the field of
respiratory diseases, the company Cohero Health introduced a spirometer with seamless

37
connectivity to a mobile platform (phone or tablet), which measures and records respiratory
strength (FEV1, FVC, Peak Flow) data of patients across the mobile platform and the cloud
(45, 75). Also, the company produces sensors that can be combined with medication inhalers
to treat asthma or COPD. These sensors register the use of the inhaler and can store the time
and location of the activation of the inhaler, thus allowing for drug adherence monitoring. The
combination of the smart spirometer and the sensor capturing timing of inhaler activation
represent essential information for clinical research, and can facilitate the development of
virtual clinical trials in the therapeutic area of respiratory diseases. Thus, the clinical team can
remotely monitor treatment adherence and data collection daily through the smart spirometer
without requiring an arduous schedule of visits by the patient at the clinical site. The Cohero
Health spirometer is validated and approved by the FDA (510 k approval) and is currently
being used in partnership with the Mount Sinai Hospital in New York to monitor treatment
adherence and determine the effectiveness of prescriptions for the treatment of asthma and
COPD (45).

All of the above cited examples require integration with a mobile platform, acting as a
conduit between the wearable device or sensor and the cloud. Providers of these platforms,
including Apple with its iOS mobile operating system and Google with its Android
platform, facilitate the development of this concept by extending their platforms to improve
clinical research. In 2015, Apple launched its Apple ResearchKit project, an open source
platform for remote collection of various data specific to certain medical conditions through
their iOS operating system (76). The open source platform allows software developers across
the globe to create mobile applications based on this platform, to improve it and allow others
to benefit from it. Apple initiated partnerships with various specialized academic
institutions across the United States to study specific diseases in the general population. Of
these, Parkinson's disease is an example where patients can use some data collection functions
from the ResearchKit platform, such as voice and dexterity tests to chart the patient's progress
over time. Studies to observe other conditions such as asthma, diabetes or epilepsy are also
underway to identify the potential of this clinical research platform. Still, the tentative and
non-validated nature of the platform constrained its application in clinical research at the
observational level. Clinical studies of interventional nature require more rigorous validation,

38
requiring additional efforts to improve ResearchKit to bring it to a level suitable for clinical
research in the pharmaceutical industry. For its part, Google has recently announced the
creation of a life sciences division called Verily, aimed to launch mobile technology
projects for solving known issues in clinical research (77). It is too early to predict the impact
of this announcement and results of the planned projects by Verily, but the potential brought
by a giant like Google to improve clinical research assisted by mobile technologies remains
promising.

Electronic data capture is therefore crucial to the development of a remote clinical trial.
In the absence of clinical research sites, remote data collection reported by the patient, via
mobile platforms or wearable devices via the cloud, becomes essential for the Remote Clinical
Trial model. Also, it allows continuous data collection and can improve the quality of the
evidence generated by clinical research. Finally, remote data collection allows patients to
participate in the study from the comfort of their homes, reducing the need to travel for visits
included in the protocol, and clearly drawing up the path for Patient Centricity in clinical
research.

3.2.3.4 Challenges and perspectives with electronic capture of clinical data

Despite the promise and enthusiasm that mobile devices and the BYOD concept
provide for the use of patient-reported data in clinical trials, a few challenges remain to be
overcome for a wider adoption of this approach. First, this approach could require the addition
of non-clinical eligibility criteria for the study, such as the need for patients to own a mobile
device, or to have internet access. In spite of the fact that internet access is nowadays vastly
widespread, and that a significant portion of the population owns one or more mobile devices
(phone or tablet) (13), this access differs across different strata of the population. This may
thus exclude patients who do not meet these criteria, based on their age group, education,
economic status or geographic location. Also, additional costs may be incurred by sponsors if
they decide to provide internet access or mobile devices or wearables to patients who would
otherwise be excluded. In addition, ethical considerations may arise concerning the incentive
to participate in the study simply to get or try a new device. Added to this is the consideration
that handheld devices are not all equivalent in terms of user interaction due to their difference

39
in screen size, position of the keyboard keys and portability among other factors. Also, some
argue that the multi-functionality of smart mobile devices can cause distraction to the patient
when filling the ePRO survey, although this is also true for paper versions, and it remains to
be seen if this distraction produces a real impact on data quality. Technological considerations
such as required disk space for mobile applications to operate and assurance of data security
and privacy as well as data encryption are also important to note. With all these potential
obstacles, ePROs and the BYOD concept remain an interesting option for clinical research
data collection, and it is clear that they represent a certain potential for improving research and
lead to patient-centered clinical research (40, 41, 42, 78).

On the other hand, the implementation of wearables in clinical research also entails
some challenges. Although many critics first point to regulatory agencies as a major obstacle,
it is important to specify that these agencies are generally open to discuss innovations for the
advancement of clinical research conduct. It is therefore false to assume that the regulatory
agency by its nature represents an obstacle to the implementation of a clinical research
strategy that involves the use of wearables. From a regulatory perspective, it is important to
ensure that the data entered via wearables are valid and robust for clinical research. In other
words, the wearable device must be regarded as a medical device if the data obtained from it
are critical for the study. Thus, the wearable device must be validated with regulatory agencies
to demonstrate that its use produces valid data for the basis of any clinical evidence generated
for the study. It must be demonstrated that the generation of these data remains valid in
various circumstances of everyday life, such as the distinction between real physical activity
and sudden and rapid movement without physical activity, for example. Manufacturers of
these wearable devices will have to devote increased attention to the demonstration of the
validity of data for a clinical research setting, and must coordinate the development of their
products together with the pharmaceutical industry and regulatory agencies.

Moreover, since the data would now be captured continuously and in an unsupervised
environment, it is crucial to ensure that the patient uses the wearable device correctly and that
he wears it constantly. Conversely, a report published in 2014 by the consulting firm
"Endeavour Partners" found that more than half of US consumers that have tried a wearable
device stop using it on a long term basis, with a third of them dropping it out completely

40
within 6 months of use (46). Although the usage context of wearables devices by everyday
consumers does not necessarily draw a parallel with the generally controlled clinical research
environment, it is important to know the reasons for lack of retention in their adoption. Among
these reasons, the ease of use for the device as well as seamless integration with smartphones
are notable factors affecting their adoption. Improving the ease of use of the wearable device
will lead to better data quality for the data captured by the device, through a proper use of it.
This applies both to the device as well as to the connected smartphone application, which
would require proper initial training for patients in a clinical research setting. In addition, the
aesthetic and comfort factors are especially important. Some of these devices are intended to
reside in palpable proximity on the patient's skin over a long period of time. This can
eventually cause skin irritation in some cases, leading to the abandonment of the device.
Finally, given that a primary goal of developing a remote clinical trial would be to minimize
disruption of the patient's daily life, it would be unsuitable for the patient to wear a device that
would be disruptive and incompatible with his daily life. For example, battery life and non-
water resistance would force the user to have to remember to frequently remove the device
and wear it again later. This disruption does not only affect consumer adoption, but would be
even more damaging to its use in a clinical trial, possibly leading to a lot of missing data. This
reasoning forces us to consider the probability of non-compliance to the study protocol in
terms of data capture with wearables, a risk which could be reduced by a vigorous risk-based
monitoring strategy.

Finally, it is important to note the inevitable challenge of analyzing the deluge of data
that would be generated by a continuous longitudinal data collection facilitated by wearables.
This represents a major change when compared with traditional data collection methods for
clinical trials, which usually involve sporadic data capture designated by planned study visits
by the clinical protocol. First, we must note the critical importance of adapting the IT
infrastructure in terms of databases to store the huge amount of data generated. Moreover, the
continuous collection of data can lead to out-of-context data interpretation, such as an
increased heart rate due to intense exercise could mistakenly be interpreted as a consequence
of treatment. Also, adaptation and further validation of data analysis algorithms are necessary
to allow proper interpretation of the results, in order to distinguish between real data and

41
ambient noise, and thus lead to robust evidence supporting the clinical study. In addition, a
culture change in the pharmaceutical industry and in healthcare will be needed, as well as the
emergence of qualified data scientists for the analysis large amounts of data to ensure the
success of adopting wearable devices in the context of clinical research.

The above mentioned challenges, however, are not insurmountable. There is clear
evidence that the actors involved in the design, manufacture and promotion of wearable
devices and smart technology demonstrate a strong interest in driving their products into the
healthcare and clinical research sectors. Thus, there is increased attention from the industry
towards the improving of wearable devices for clinical research purposes and overcome the
perceived difficulties. The contribution of engineering in electronics manufacturing already
aims to improve the battery life of small devices for example, and this could probably also be
applied to wearable devices. Another innovation in the horizon is the production of a wearable
device using a battery powered by the energy emitted by the body of the wearer (47). Also, the
myth which claims that the requirements of regulatory agencies act as a major obstacle to the
use of mobile technology for clinical research is not sustainable. Instead, the FDA for example
is in favor of the adoption of these technologies to improve and facilitate progress in clinical
research, and encourages sponsors to take the initiative in this direction (57). In addition, the
rapid growth of wearable devices in hospitals could lead to their designation as part of the
standard of care in the management of health conditions in certain therapeutic areas. This
designation could help persuade the pharmaceutical industry to gradually incorporate the use
of these devices in clinical research. Undoubtedly, the rapid advancement of mobile
technology and wearable devices will inevitably pave the way to their plausible use in clinical
research. It will remain for the pharmaceutical industry to adapt its business culture and
prepare the basic infrastructure required for the expansion of these technologies in clinical
research.

3.2.4 Telemedicine, Monitoring, and Drug Adherence

Telemedicine is gaining increased popularity in healthcare to provide medical

consultations to patients with their doctors from the comfort of their home. Being a fairly

42
established concept in healthcare, it is possible to anticipate its usefulness in clinical research,
to allow the conduct of clinical trials more focused on the patient.

As mentioned several times in previous paragraphs, the non-clinical and unsupervised

setting associated with the remote clinical trial thus requires a major emphasis on clinical
monitoring. To ensure clinical data quality, it is not sufficient to rely on an improvement in
clinical data capture, but it is also necessary to have a robust clinical monitoring strategy.
Traditionally, clinical trial monitoring is done by a process that involves a complete audit of
all source data through SDV to confirm data integrity. As described earlier, this long and
arduous process can be greatly reformed by risk-based monitoring (RBM) and remote
monitoring for remote clinical trials.

Another known issue in clinical research is treatment adherence for patients to ensure
that clinical data is correctly interpreted. According to a report by the World Health
Organization (WHO), it is estimated that 30-50% of patients do not adhere to treatment as
prescribed by their healthcare professional (48). In clinical research, this problem is a major
challenge for the pharmaceutical industry, which necessarily depends on the clinical data
generated by the study. Thus, if patients are non-adherent to their treatment while claiming
they are, this represents a partial bias that may affect the interpretation of results. This could
come back to haunt clinical research sponsors post product marketing, during the occurrence
of adverse effects related to the drug and not detected during clinical research phases,
probably due to non-adherence. The costs of non-adherence to treatment are estimated to be
between 100 and 300 billion dollars annually in the United States (49), which explains why
this is still extremely important for the pharmaceutical industry.

3.2.4.1 Telemedicine

The idea behind the merger of clinical research and telemedicine is not new. A simple
literature search reveals that the idea was under discussion in scientific journals already in
1996 (50), and perhaps even before. In fact, some precepts of telemedicine are already in
clinical research today where patients sometimes have to take phone calls planned by the study
protocol to follow up on their condition. In addition, telemedicine is practiced for several years
in the healthcare sector in the United States (51), where some patients follow up with their

43
doctors via a video conference session for example. It is therefore valid to anticipate the
implementation of telemedicine concepts also in clinical research.

Telemedicine involves patients having consultation with a healthcare provider via a

video conference session from the comfort of their homes. This virtual interaction via video
conferencing can take the same amount of time as a normal traditional consultation with a
doctor and may result in a diagnosis and a prescription if necessary. Also, the telemedicine
platform can be enhanced by the ability to obtain medical device data to measure blood
pressure for example, or examine heartrate. Moreover, this platform can also be utilized for
the realization of virtual visits ("e-visits") during the clinical study, where the principal
investigator and the clinical team have a direct follow-up with the patient, as planned by the
clinical protocol. Thus, patients benefit from this approach since they no longer have to travel
regularly to the clinical site for the protocol visits. This approach allows for more patient-
centered clinical research. Also, removing the burden of regular travel for the patient could
probably allow more regular follow-ups with the patient to maintain engagement during the
study. Furthermore, this would allow the participation in the study for patients geographically
distant from the study site.

For these reasons, telemedicine is not only a unique opportunity for the development of
a remote clinical trial but also an indispensable asset to its feasibility. There are still however
some barriers to its adoption in clinical research. A major concern with this concept is the
notion of the equivalence between a remote visit and live site visit with the investigator. A
study assessing the equivalence between telemedicine visits and clinic visits for patients who
underwent radical prostatectomy showed that both methods are equivalent in terms of
efficiency and patient and physician satisfaction (52). Also, as anticipated, the study shows
that costs are reduced with telemedicine. It is though still unclear whether this demonstrated
equivalency in a healthcare setting is also valid for clinical research. The applicability and
relevance of telemedicine may well depend on the condition being treated, whether in
healthcare or clinical research. For example, for some serious conditions like late-stage
cancers, there is little room for telemedicine. Moreover, despite the demonstrated equivalence,
it is legitimate to question the quality of the physician-patient interaction in a remote context
via telemedicine, a contact that is generally maintained in a context where the doctor can

44
physically examine the patient. This may result in attenuation of the placebo effect possibly
due to less contact with the clinical team compared to a planned protocol clinical visit. This
possibility should be considered when analyzing the results of the remote trial and the impact
on the placebo effect should be investigated. Legal and regulatory considerations are also
noteworthy, since the medical responsibility is not clearly defined: is the patient under the
supervision of the principal investigator following the patient remotely, or in the responsibility
of his primary care physician who is not associated with the clinical trial? One solution to this
dilemma may come from the formation of a partnership between the two institutions for a
model of care for the study patient in case of any emergency, involving the local primary care
physician and the principal investigator remotely. Also, specific state, province or territory
legislations could become an obstacle to the provision of health care by an out-of-state
practitioner. These legal considerations could be resolved by establishing mutual recognition
between states, provinces or territories, enabling healthcare providers (doctors, nurses, clinical
staff, etc...) to practice their medical profession through telemedicine, for the realization of a
remote clinical trial. In addition, there are already efforts in the US and Canada to reduce legal
barriers to the implementation of telemedicine (59, 60). The generally slow and arduous
process for the adoption of a new legislation of this magnitude requires harmonization
between governments that are often not aligned, which does not seem too easy to accomplish.
Despite these obstacles, the application of telemedicine is absolutely necessary for the success
of the remote clinical study.

3.2.4.2 Centralized Remote Risk-Based Monitoring

Risk-Based Monitoring (RBM) is the practice of establishing a clinical research

monitoring plan based on the potential risks involved in the conduct of the study.
Traditionally, the monitoring plan requires frequent visits to clinical sites by a study monitor
to verify the integrity of documents and detect any errors or deviation from the study protocol
via a tedious process known as Source Data Verification (SDV). In contrast, RBM requires an
assessment of all the potential risks of the study prior to its start and a ranking of these risks in
order of priority. This risk assessment paves the way for a more targeted monitoring strategy
to potential problems with a greater likelihood and a greater impact on the study results. With
the support of informatics technology, and electronic data capture at the source (e-Source)

45
described in the previous chapter, it becomes possible to get direct real-time access to clinical
data in addition of getting more information on the study conduct as per the clinical protocol.
The practice of clinical monitoring thus evolves from a reactive activity happening after the
events, to a proactive activity, identifying all events of the study conduct in near real-time.
This practice usually requires the identification of several key risk indicators that will be
measured, such as the number of adverse events, the number of errors in the CRF data, the
protocol compliance rate, etc... Another RBM technique employs statistical modelling
methods to detect the occurrence of anticipated risks. This technique requires the registration
and identification of all the parameters recorded during the execution of the study and the
application of statistical models to identify any abnormalities.

Risk-Based Monitoring has gained more scale and popularity in recent years,
motivated by specific guidelines issued by regulatory agencies such as the FDA and the EMA
(23, 79). Therefore, several clinical research informatics solution providers emerged offering
different platforms to promote the implementation of RBM. It is therefore permissible to
believe that solutions offered by these different vendors will pave the way to the practical
realization of this concept for the clinical trials conduct and monitoring today and in the near
future. Some important considerations are needed when selecting a technical solution to
facilitate RBM implementation. The solution must support the identification, assessment and
categorization of risks for a clinical trial, and can keep an audit trail and archiving of events
that may influence the impact of these risks. Also, the solution must provide the capabilities to
configure specific alerts based on the occurrence of identified risks, and be able to clearly
determine necessary actions for the mitigation of such risks. Finally, it must have analytical
capabilities to identify risk trends to allow proactive prevention of negative impacts on the
study. Through an integration of multiple data sources and graphical data visualization, the
solution would allow clinical monitors to predict and monitor the impact of these risks and
take proper actions when necessary.

Developing a remote clinical trial is not unlike the traditional clinical trial in terms of
the necessity for clinical data and study conduct monitoring. In fact, performing RBM
remotely is essential for the remote clinical trial model. To successfully achieve this approach,
we must first identify potential risks introduced by the distant nature of the trial, where

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patients are not in proximity to the central coordinator study site. For the remote trial, these
risks can be divided into two groups: risks associated with the general conduct of clinical
research, similar to the traditional clinical trial, and risks associated with of distant nature of
the trial, unique for the remote clinical trial model. Risks can be classified into five major
categories:

Risks related to the conduct of the study: rates and methods of patient
recruitment, screening and consent, protocol deviations, patients lost to follow-
up, etc

Risks related to clinical data integrity: inaccurate, erroneous or absent data

capture, fraud, etc

Risks related to patient safety: tracking of number and nature of adverse

reactions, etc

Risks related to the logistical study conduct: Staff turnover during the study,
training, skillset and certification of study staff, contingency and backup
strategies for technology failures, call center measurements, etc

Risks related to treatment adherence: wrong dose taken, wrong time of taken
dose, etc

For each of these categories, the remote trial clinical team must have a defined strategy to
identify and mitigate risks specific to the study in question that are amplified by the remote
setting of the study.

First, for the risks related to the conduct of the remote study, the patient recruitment
and electronic informed consent strategies described above can have an impact. It is clear that
an adequate and timely patient recruitment is a key indicator for the success of the study. From
there, it is therefore important to monitor the rate of patients recruited and enrolled for each
strategy described earlier, and adjust the strategy as necessary. Thus, in the event that the data
indicates poor patient recruitment, the clinical team may decide to focus its efforts on
improving a particular strategy and reduce them for another, all depending on the situation.
The proper informed consent can also be monitored remotely by checking the statistics of the

47
electronic consent process for each patient, such as time spent on each section, the questions
asked by the patient, the highlighted unfamiliar terms in the text or the knowledge review
results to check understanding. Although these data are not needed for the regulatory dossier,
they can be a key asset for monitoring study conduct integrity. Also, with electronic informed
consent, it is easier to determine which patients need to be re-consented following a protocol
amendment. With such tracking, it becomes possible to know the accurate time when patients
give their consent, and if the data entered following a protocol amendment was made before or
after the re-consent. Moreover, in a remote study environment, identity fraud remains a
significant risk that must be monitored. Before the start of the informed consent process, it is
imperative to verify the patients identity and confirm that they are really who they claim to
be. A potential solution to this problem can be to verify the persons identity through known
methods from credit agencies. These methods have improved in recent years and are used to
ask targeted questions to the person, related to their social security number for example to
validate their identity. This must be done by assuring complete privacy and confidentiality to
the patient, preventing access to this information for the clinical site or the sponsor, and
limiting access to the audit agency for identity verification. Thus, sponsors and clinical sites
will only receive an indication of the validity of the patient's identity (valid / invalid), without
obtaining private information such as social security number or others. Also, it is not
unexpected to use a video session between clinical staff and the recruited patient to verify the
person's identity before obtaining their consent. Alternatively, informed consent can be made
from the patient's home, in the presence of a clinical staff representative, who may therefore
verify the patients identity on the spot. This demonstrates that the development of the remote
study requires monitoring and risk mitigation measures from the very beginning of the
interaction with the patient, not just during scheduled visits to clinical sites by the study
monitor. Thereafter, any protocol deviation and / or patient lost to follow-up may be properly
detected by programming the different events of the study in the risk-based monitoring
platform. A good example would be to capture the event of a missed visit by telemedicine, or
a questionnaire unfilled at the proper time, constituting a protocol deviation. Missed study
visits are recorded for each patient, and the integration of the telemedicine system with that of
risk-based monitoring is a unique opportunity to guarantee the accuracy of information
relating to the conduct of the study. This information is easily accessible to the clinical team
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through alerts, tables and figures on the remote monitoring system, updated dynamically
according to changes in the study.

Risks related to clinical data integrity play a critical role for the success of the remote
clinical trial. The impact of these risks can be greatly influenced by the electronic clinical data
capture at the source. However, these risks still exist despite improved data capture through
eSource. First, the collection of fraudulent or invalid data represents one of the greatest
concerns related to clinical research in general, and probably more for a remote trial. In an
article published in 2005, a survey of authors of clinical trial reports indicates that 17% of
them claim to be aware of fraudulent data recorded during a clinical trial in the previous 10
years (53). Fraudulent data can be recorded by the patient or by the clinical study personnel.
The problem of fraud committed by study personnel can be greatly reduced by capturing data
remotely via mobile devices and the BYOD concept, provided that the systems for recording
data are in line with regulatory requirements (21 CFR - part 11) (72). In contrast, it is
reasonable to believe that the unsupervised context of patients reporting continuous data
during a remote clinical trial can open the door for registration of fraudulent data by the
patient. For example, it is possible that the patient places the activity monitoring wearable
device on his pet or another person who may be more active than him/her, to generate the
perception that he/she is an active patient. This risk could be mitigated by developing
algorithms that can distinguish between the typical movement patterns of a human versus that
of the animal, and raise an alert on the remote monitoring system if necessary. Also,
monitoring strategies by statistical methods could help detect fraudulent data outliers that are
detected by the statistical model that is used. Another strategy for mitigating this risk could be
to register all withdrawal events of the wearable device and trigger an alert when an anomaly
is detected. A visible alert on the monitoring system could also be triggered if an omission in
data recording is detected, caused for example by a patient forgetting to wear the device again
after removing it. This is also applicable to patient-reported data through a validated
questionnaire on their smart device (BYOD); an alert can be triggered to remind the patient to
complete the questionnaire in the required time interval. The risk of missing data by wearable
devices can also be mitigated by the remote monitoring of the devices battery life, the
verification of its Internet connectivity or the constant calibration of the device to confirm

49
proper operation. All these measures require the validation of wearable devices for clinical
research and the collaboration of wearable device vendors to minimize the potential impact of
risks of fraud or missing data. Proper integration between electronic data capture and remote
monitoring systems is therefore fundamental to the success of this risk mitigation strategy to
control the risks that could occur from remote data collection through wearable devices or the
BYOD concept for a remote trial.

Risks related to patient safety also represent a key role in the success of the study, and
can be closely monitored with a robust risk-based monitoring strategy. First, as with the
traditional clinical study, it is essential to have in place an adverse events reporting program,
where the principal investigator, clinical staff and patients can report any adverse reactions
occurring during the study. The remote monitoring system must be able to easily present and
classify all adverse events reported by class and by patient, and supporting a rapid response by
clinical staff to protect the patient if necessary. Thus, to improve patient safety, telemedicine
sessions with the principal investigator of the study can be made remotely as needed to discuss
the noted adverse event with the patient. In addition, a partnership with the patients primary
care physician must be established if the patient requires immediate care following an adverse
event. These measures can help reduce risks of harm to patient safety for all patients
participating in the remote trial, while providing the ability to remotely monitor the adverse
events profile of the treatment during the course of the study.

Risks related to the logistics of running clinical trials can be reduced by the full
representation in the risk-based monitoring system of all clinical staff involved in the study. A
profile of all trainings taken by clinical research staff and their experience level can be traced
through personnel changes that may occur during the trial. Also, any activity in the clinical
protocol should be attributed to a person of the study, which allows tracing a link between the
level and the nature of the procedures performed by someone with their level of seniority,
experience and training. In addition, a contingency plan is absolutely necessary in case the
technology fails. These technology failure events should be monitored and must be remedied
if found frequently. Finally, all the necessary measures to monitor a call center should also be
part of the risk based monitoring plan. Measures such as call resolution rate, number of calls,
patient questions, etc. must be considered and monitored to mitigate risks associated to them.

50
 Risks associated with treatment adherence can be monitored remotely through the use
of some modern platforms useful for clinical research (80). These risks and their mitigation
will be discussed in the next paragraph.

3.2.4.3 Treatment Adherence Assisted by Technology

One of the integral components of the monitoring of clinical research is to confirm the
integrity of evidence generated; specifically, the demonstration that patients are indeed
adhering to treatment. As noted earlier the non-adherence to treatment presents several risks to
the clinical research sponsor, and must be closely monitored during the study. Typically,
adherence is monitored by the clinical team counting down the remaining medication at the
end of the study. Other methods are based on surveying patients regularly to determine their
adherence to treatment, or having patients keep a daily journal writing the time and dose taken
for treatment. Although these techniques are quite common in clinical research, they are not
flawless in giving a real indication of adherence. In addition, it is clear that these techniques
are not adequate in the conduct of a remote clinical trial. Several technology-assisted methods
are suitable alternatives to measure adherence in a remote trial setting. First, a simple but
effective method uses text messaging or any other form of messaging to send patients daily
alerts to promote treatment adherence. This method falls into the category of behavioral
intervention, involving the influence of patient behavior through periodic alerts, thus
contributing to a patient's better improved overall engagement with the study.

Another way to monitor adherence to treatment would be through sensors implanted in

the medication container; smart bottles of pills or capsules or the inhaler when treatment is
inhaled (80, 81). This method allows registering a timestamp at the opening of each bottle, as
well as recording its weight after its closing, thus giving evidence that the pill or capsule is
removed from the container at a specific time. The concept is similar for inhalers: a timestamp
and possibly even the location are registered at the activation of the inhaler. These timestamps
can be synchronized via a mobile app to the cloud and compiled individually for each patient.
These two techniques represent a major advance in measuring adherence remotely, but do not
guarantee that the patient is actually taking the treatment. Accordingly, nothing prevents the
patient from taking the medication out of the bottle and throwing it in the trash for example,

51
which would obviously give a false measure of adherence. However, this argument is also
valid for the traditional techniques of pill counting or simply relying on the patient's statement,
both techniques depending on the patient's good faith and willingness to give accurate
information. Hence, it is reasonable to consider the addition of sensors on the medication
containers used in the study to be a better measurement of treatment adherence, and several
solutions already exist on the market to meet this end.

A third technique for measuring treatment adherence is based on a derivative of

telemedicine combined with artificial intelligence. The company AiCure recently produced a
platform that can be started from a mobile app to detect the uptake of the studied treatment
using a camera and smart algorithms within the app (82). Indeed, this platform requires the
patient to take the medication in front of the camera using a smart device that records the act
of taking the treatment. A smart algorithm embedded in the app recognizes the patient, the
treatments digital signature visible to the camera and the complete treatment administration,
whether oral, sublingual or respiratory through inhalers. Everything is video-recorded with a
blurring of the visible image of the patient's face, ensuring anonymity and confidentiality, and
is synchronized to a cloud database that is accessible to the clinical team on a portal. With this,
the clinical team obtains a specific treatment adherence profile for each patient, without
breaching patient confidentiality and privacy. This is important since some patients may be
reluctant to use such a platform, especially if they want to avoid having images including
family members, for example, accidentally captured and permanently stored in the system.
This solution seems fairly sophisticated, but may be a primary asset for a remote clinical trial
to measure treatment adherence remotely.

Obviously, regardless of which treatment adherence technique is used, it cannot be

considered uniquely in itself in an isolated setting, but should rather be included in the overall
monitoring strategy of the remote trial. When properly implemented, the measurement of
treatment adherence further controls the perceived risks brought by the realization of a remote
trial and helps in generating robust clinical evidence. For this, we consider the measurement of
treatment adherence facilitated by technology a vital component of the monitoring strategy for
remote clinical trials.

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 3.3 Integral representation of the Remote Clinical Trial model
Having described the necessary components of the remote clinical trial, it is now
appropriate to view a full representation of the model that includes all of these components. To
do this, we will describe the synopsis of a hypothetical remote clinical trial for the treatment of
COPD in which the drug is administered via a specialized inhaler device. This hypothetical
study will be designed by applying the remote clinical trial model. It is assumed that this study
is a phase III trial, to evaluate the effectiveness of the study drug compared to a reference
treatment, and has between 100 and 200 patients.

3.3.1 Diagram of the Remote Clinical Trial model

Figure 2 illustrates a complete diagram of the remote trial model, featuring all the
components described above. In the diagram, patients participate in the remote clinical trial
fully from the comfort of their homes, as shown in point 3.

Figure 2: Integral representation of the remote clinical trial model, with one central coordinating site

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 3.3.1.1 One central coordinating site

At the beginning of this manuscript, it was noted that a remote clinical trial is, by
definition, a clinical trial that eliminates or significantly reduces the contribution of clinical
research sites, keeping one central coordinating site for the study. This coordinating site is
crucial for the development of the remote clinical trial because the whole study is based on
this sites operations and its diligent coordination. The remote trial is therefore centered on
patients because it eliminates the multi-centricity for sites while allowing patients to
participate in the study without necessarily being located at geographic proximity of clinical
sites. It is therefore important that the selection of the site and the principal investigator be
made with due diligence by the sponsor, in order to ensure the success of the study. The sites
ability to manage a new concept like that of the remote clinical trial model and their agility in
terms of adoption of new technologies are important aspects to consider in site selection. As
will be described in the following paragraphs, this site will be the main reference for the
patient and will perform all clinical activities during the study. Above all, this site will
perform the telemedicine study visits and collaborate with the CRO to perform central
monitoring of the study as well as managing the adverse events reports and providing proper
support for patients. The management of clinical supplies, medical devices or wearable
devices will also be done through this site and facilitated by a partnership with a clinical
supplies services company.

3.3.1.2 Patient Recruitment Strategy

Patient recruitment for the hypothetical COPD trial will be initially based on dedicated
social networks like MyCOPDTeam from MyHealthTeams (33, 84) and
PatientsLikeMe (32), as well as the U.S.-based COPD foundations social network (83).
The strategy involving social networks does not stop at these dedicated social networks, but
also involves specialists to recruit patients through common social networks such as Facebook
and Twitter. The strategy also includes the establishment of partnerships with health insurance
providers to find potential patients for the study. This involves a partnership with companies
such as Optum and/or Anolinx to find potential study patients from their electronic
medical records (EMR) or by their health insurance claims. Finally, a partnership with vendors

54
providing digital tools like TrialReach and CAVII to better target patients through mobile
applications would also be beneficial for the success of the patient recruitment strategy for the
remote clinical trial. It is not absolutely necessary to be limited to digital and mobile
approaches such as those mentioned above. Thus, it is allowable that recruitment for the
remote clinical trial may resort to some traditional approaches to generate more traffic to the
study website such as advertising on traditional media or the internet, and partnerships with
physician networks. The ultimate goal would be to get the most possible potential patients
registered via the study website and move to the next steps which are patient screening and the
beginning of informed consent.

3.3.1.3 Screening, ID verification and Consent

Once a potential patient is referred to the study website, they receive all the critical
information about the study. They also obtain the necessary information to establish direct
contact via email or telephone with the clinical study recruitment team. The individual is
encouraged to register as a potential patient in the study and start the initial screening process
to determine eligibility. This process can also be started outside the study website, through
platforms such as TrialReach or CAVII, or even through dedicated COPD social
networks cited above. The screening process includes general questions to determine
eligibility and specific questions about the patient in order to validate their identity. Once this
step is completed and the patients study eligibility and identity are confirmed, a call from a
clinical study team representative is initiated to establish direct contact with study staff. This
allows the patient to have confidence in the existence of a real clinical study and for the
clinical team to confirm the existence of the patient and match his data entry made on the
study website with a real person. This contact also provides the opportunity for the patient to
get more information about the study and ask preliminary questions to determine his/her
interest to continue the process. If the patient decides to continue, he/she receives a private
secure link from the study representative to formally perform the electronic informed consent
process. Alternatively, an iPad can be mailed to the patients home, where they can access the
e-Consent application. The electronic informed consent platform can be provided by known e-
Consent vendors such as Mytrus or Enforme, and is defined specifically for the study,
containing the integral text of the informed consent form. It can also present audiovisual

55
content, the possibility for the patient to mark unfamiliar terms and register questions as well
as perform a short knowledge review test at the end to confirm patient understanding.

Electronic informed consent can be performed through a mobile application accessible

via smartphone or tablet, or a private secured website accessible via a client machine, and only
visible to the patient using a password. If the patient agrees to participate in the study after the
electronic informed consent process, another direct contact is established with the study staff
via a phone call or an audiovisual conference call where the patient can ask any questions and
perform the signature of the document. The patient's signature is on the informed consent
electronic platform during the phone or conference call between the patient and clinical staff
or the principal investigator. The patients signature is immediately followed by the signature
of the principal investigator and witnessed by a third party if necessary. Alternatively, the
process of informed consent and electronic signature may be performed at the patient's home
in the presence of a clinical staff representative such as a nurse, and having the principal
investigator available by conference call. After that, the patient is considered to be enrolled in
the study. According to the protocol, if it is deemed necessary to perform medical procedures
for measuring the patient's baseline, the patient may have to attend a local clinic, or get a visit
from a phlebotomist at home for blood work. This step can also be done prior to informed
consent, if it is considered critical in determining the patient's eligibility for the study.
Following the inclusion of the patient in the study, the study medication, inhaler and any other
medical or wearable devices are sent to the patient by a third party company affiliated with
the sponsor and specializing in clinical supplies. Finally, also according to the protocol, the
patient agrees to adhere to a specific e-visits schedule facilitated by telemedicine via the
coordinating site and the studys principal investigator.

3.3.1.4 Data Collection

According to the study protocol, a washout and basic screening period may be
expected. This means that the patient cannot receive the study drug until a few weeks of
follow-up after Day 0 (date of enrollment in the study). The hypothetical COPD study aims to
determine the progress of the patient's respiratory strength during treatment, as well as
determining the patients level of physical activity and sleep quality throughout the study. To

56
do this, the protocol includes the use of a smart spirometer, (i.e. Cohero Health) for
measuring the primary endpoint of the study, which is the patients respiratory strength
(FEV1/FVC, Peak Flow). The patients level of physical activity can be captured via an
activity monitoring device as a secondary endpoint. The key to the success of data collection
through these wearable devices is their portability, comfort and battery life for each device.
Thus, the Garmin Vivofit wearable device is selected for activity and sleep monitoring, with
a 1-year (365 days) battery life. Finally, another secondary endpoint will be captured through a
validated questionnaire for quality of life, provided to the patient through his smart phone
(BYOD). The questionnaire will be the (McGill COPD Q) (54) instrument to measure patient
perceptions about the improvement of their condition. Other questionnaires could be used if
necessary, but for the hypothetical case of this study, we will limit ourselves to this one
questionnaire.

The study sponsor will need to have in place the necessary IT infrastructure to be able
to capture all this continuous data flow through the cloud. To get the patient's baseline data, a
2 weeks period of continuous data collection is established at the start of the study, before any
administration of the study treatment. Subsequently, the study treatment will be started and
remote data collection will continue in the same way. It is important to clarify that the patient
will require adequate training to use the spirometer and the wearable device. This training is
critical and necessary to the success of the study, and will be provided by a study nurse at the
patients home at the initial study visit. This could also be done remotely via the telemedicine
platform, but it is rather recommended that the initial training happen in a live interaction with
the patient.

Finally, a good patient engagement strategy is required to ensure the patient takes the
study treatment regularly as stipulated in the protocol, and provide the necessary
measurements regularly with his/her smart device and reported by the spirometer.
Additionally, an adequate monitoring strategy will be required to regularly remind the patient
to adhere to the protocol, through mobile alerts via the study app.

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 3.3.1.5 Monitoring, Quality Assurance and Patient Protection

The success of the remote clinical trial requires an adequate monitoring strategy to
minimize the impact of risks related to the implementation of the remote trial model. This
strategy emphasizes the importance of the central coordinating site to the study, which
performs many of the monitoring activities on a daily basis during the course of the study.
These activities include monitoring treatment adherence remotely, monitoring and support of
patients through the telemedicine platform and the reporting of side effects. The central site
also establishes the relationship with the Institutional Review Board (IRB) for any necessary
amendment to the protocol. The study sponsor is responsible for central risk-based monitoring,
and will have access to anonymous data with regards to treatment adherence and side effects
reports.

Regular patient follow-up is enabled by the implementation of a telemedicine platform

facilitating regular contact between patients, the clinical team and the principal investigator.
The platform used serves as the central portal to manage the clinical trial for all enrolled
patients. It will allow patients to schedule their planned e-visits with the clinical team as per
the trial protocol. Also, using a mobile application, it will better engage patients during the
study, through alerts and reminders for various activities related to the study conduct such as
taking medication, filling the questionnaire and using the digital spirometer and the wearable
device. Moreover, the study sponsor must have predetermined the major risks and their
potential impact before the start of the study. These risks will be represented in the RBM
platform, and all data collected during the study will be monitored by the central clinical site
staff in order to preserve the quality and integrity of study results. Drug adherence is measured
through a sensor installed on the inhaler, registering the time and location of activation of the
inhaler to administer the study medication. If deemed necessary, the clinical team may utilize
a drug adherence platform assisted by the smartphone camera, such as the AiCure platform,
which video-records the daily event of taking the medication. This treatment adherence data of
individual patients may also be visible to the study sponsor, while maintaining anonymity and
confidentiality of patients no patient identifiable information is made available to the
sponsor. Finally, all adverse events occurring during the study will be reported and compiled
by the clinical team at the central coordinating site. Patients and their families will be

58
informed of the procedure for the communication of adverse effects to the central coordinating
site. Patients and their families will also have direct access to a call center where they can
report any adverse effects. Also, each patient can report to a clinic or hospital in the vicinity of
their home in the case of serious adverse effects. Any adverse effect will be followed by the
sponsors pharmacovigilance department as per the ICH E2E guidelines (85).

3.3.1.6 Patient Engagement in the study

As noted earlier, the remote clinical trial requires good patient engagement to lead to
the success of its development. Patients feel engaged with the study when they have the
opportunity to be frequently informed of the study activities through reminders and alerts.
Also, with the telemedicine platform, the patient has the opportunity to contact the clinical
team when necessary, and to have clinical follow-ups by teleconference at specific intervals
set by the study protocol. The telemedicine platform is available to patients via a mobile
application, and provides access to a central portal at their fingertips, for obtaining information
about the clinical trial. Finally the clinical team may decide to employ techniques to influence
specific patient behavior regarding their participation in the trial, such as having a treatment
adherence ranking for each patient with a points system. The adherence score of each patient
would be visible on the study portal, and patients could see how they rank compared to other
patients in the study, all while preserving anonymity without publishing patient identifiable
information. This technique, also known as gamification, has been demonstrated to induce a
cohort of people in adopting certain behaviors or change certain habits (55).

3.3.2 Alternative to the Remote Clinical Trial model: the Hybrid model

As an alternative to the completely remote model, a hybrid model may facilitate the
gradual adoption of remote trial components for the pharmaceutical industry. Figure 3
illustrates a complete diagram of the hybrid model as an alternative to the remote trial model.

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Figure 3: Integral representation of the hybrid model, with the presence of multiple sites

The hybrid model is different from the completely remote model, in that it slightly
relaxes the principle of non-participation of multiple clinical sites for the study. Consequently,
a clinical trial applying the hybrid remote model can be used with several clinical sites
scattered geographically, while maintaining as many as possible of the components described
for the completely remote trial. Thus, patient recruitment can be done through similar methods
described for the remote trial, but also having access to patients referred to the individual
clinical sites. This would allow a better distribution of the selected study population, not
limited only to patients with a certain comfort with technology or patients registered in
dedicated social networks. This would contribute to improving the generalization of the study
results by better randomization of patients throughout the general population. Electronic
informed consent remains unchanged and applicable with the hybrid model as in the
completely remote model. Data collection with the smart spirometer, wearable device and the
quality of life questionnaire also remains unchanged with the hybrid model as in the

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completely remote model. Proper risk-based monitoring in the trial and the telemedicine
platform would also be used in the hybrid model to ensure data integrity, patient protection
and patient engagement in the study. A key difference is that the patient also has a direct and
physical contact with the clinical site team, having a combination of traditional visits to the
clinical site and e-visits. The inhaler containing the study drug, the smart spirometer and the
wearable device are delivered to the patient during the initial visit instead of being shipped.
However, to reduce the burden associated with the patients participation in the study, the
study protocol for the hybrid trial aims to minimize the number of physical visits (i.e. only two
visits: the baseline and final visit), while keeping constant follow-ups with the patient through
electronic visits via the telemedicine platform. The approach of the hybrid model enables
sponsors of clinical research to gradually move towards the completely remote trial model by
applying its individual components, and thus lead to a smoother long-term transition.

3.3.3 Comparison between the Remote and Traditional Clinical Trial

models in clinical research

Table 2 summarizes the points mentioned in the preceding paragraphs by comparing

the components of the remote trial model and those of the traditional clinical research model.

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Table 2: Comparison between the remote trial model and the traditional trial model in clinical research,
for each of the components

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 4. Discussion

4.1 Practical Considerations for the application of the Remote

Clinical Trial model
The remote clinical trial model is not suitable in practice for all forms of clinical
research. In some cases it is difficult to apply a completely remote model, especially when
patient safety may suffer. For example, when the severity of the studied condition is
considered acute, as in oncology, it would not be desirable to separate the patient from the
clinical site for proper treatment. There are also other practical considerations to contemplate
for the application of the remote trial model in clinical research. The next few paragraphs will
discuss these considerations.

4.1.1 Clinical Considerations

Clinical research conduct to investigate a new treatment or a new procedure typically
follows a standardized scientific approach and a general structure clearly defined by regulatory
institutions. Thus, the scientific method and the formulation and testing of a hypothesis are
usually an inherent part of a clinical trial. Also, it is well known that the development of a
drug for commercialization must go through the three major phases of clinical research prior
to submission to regulatory agencies. Conversely, specific elements of clinical research often
differ across studies depending on the study condition, therapeutic area, phase of clinical
research and interventional or observational nature of the study. Therefore, it is important to
review these different clinical considerations prior to the application of the remote trial model.
Firstly, all clinical research must primarily ensure the protection, safety and welfare of
patients. This equally holds true whether conducting clinical research in the traditional or the
remote trial model. Therefore, the main issue that remains before designing a clinical trial with
the remote trial model is to characterize the potential risks on safety, security and well-being
of patients. With this process, the nature and condition of the studied disease is a determining
factor in the decision to design the trial by the traditional or the remote model. When the
nature of the studied disease poses a serious mortality or disability risk to the patient, the
remote trial model becomes a less attractive option. In general, when the risk to the patient

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welfare and safety is deemed significant, the remote trial model is not well applicable. For
example, insufficient safety data for the study drug, especially when it comes to a new class of
medication with a new target, makes this a rather significant risk to patients and renders the
remote trial model less suitable. In contrast, if the clinical trial involves a study drug of a well
characterized class, the remote model can then become more interesting. Furthermore, chronic
diseases can represent a major opportunity for the remote trial model. Besides the decreased
imminent mortality risk for chronic conditions, patients of such diseases are generally well
accustomed to their condition and are generally better informed about it. This enhances the
opportunity of applying the remote trial model for chronic conditions, particularly with an
anticipated better patient engagement vis--vis their condition.
The therapeutic area also presents an important factor to consider when designing a
clinical trial and the decision of the model to apply. According to the CenterWatch
organization, there are 31 therapeutic areas in clinical research (56) (see Appendix I for a
complete list). According to our analysis, approximately two thirds of therapeutic areas
contain conditions that would qualify for the application of the remote trial model. Here is the
list among the therapeutic areas which are less feasible with the remote trial model:
Infectious Diseases: depending on the severity of the disease, the risk of epidemics
and contagion makes the remote trial concept more difficult to apply. Also, patients
with infectious diseases may require additional treatment requiring interaction with
a clinical site, and some infectious diseases pose a significant risk to the life and
well-being of the patient. Finally, measuring the progression of an infectious
disease in a clinical trial often requires specific procedures requiring the
intervention of a health care professional and the use of specialized instruments
such as DNA sequencing and analysis.

Healthy Volunteers: clinical research involving healthy volunteers is often

performed in the context of a Phase 1 clinical program to examine the safety and
adverse effects of an escalating dose of the investigated treatment. Thus, these
studies are usually performed in a clinical setting where patients are monitored
during a given period. Therefore, the safety and well-being of healthy volunteers in
Phase I remains the priority in these studies, and the elevation of this risk in the
investigation of a treatment for the first time in humans makes the application of
the remote model less likely. In cases where the intervention under study does not
pose a risk to the welfare of the patient, such as the effect of exercise, nutrition or
taking vitamins, it is conceivable that the remote model can be applied.

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 Hematology: this therapeutic area includes conditions related to blood tissues such
as anemia, blood clots, leukemia and disorders in red and white blood cells. Some
of these diseases represent a risk to the life and well-being of the patient, and may
also require specialized procedures for the analysis of blood tissues, making this
therapeutic area less attractive for the remote trial model.

Hepatology: diseases of the liver, pancreas (excluding diabetes) and gallbladder

may also require specialized procedures, which may require the involvement of a
clinical site, rendering the remote trial concept inapplicable.

Nephrology: this therapeutic area mainly includes diseases of the bladder and
kidneys (and other cancers), kidney stones and urinary tract infections. Again, not
only these diseases are often accompanied by acute and intense pain, but may also
require specialized procedures such as dialysis, thus limiting the application of the
remote trial model.

Obstetrics/Gynecology (Womens Health): for obvious reasons, everything related

to pregnancy and childbirth requires close monitoring in a specialized institution,
notably to ensure the welfare of the mother and the newborn child. Moreover,
gynecology also often requires specialized procedures restricting the application of
the remote trial model.

Oncology: cancerous diseases are often a heavy burden on patients. In addition, the
treatment of cancer by chemotherapy or radiation is often very toxic and produces
adverse side effects requiring close patient monitoring. Furthermore, the detection
of the progression of the disease cannot easily be made with a portable or wearable
instrument or device, requiring rather sophisticated instruments and sometimes
even surgery. For these reasons, oncology represents a barrier to the
implementation of the remote trial model.

Pediatrics and Neonatology: as for obstetrics, conditions related to childbirth and

young children may need physical interaction with the clinical study staff,
particularly to ensure the welfare and safety of the child. In addition, certain
childhood diseases can be fatal and therefore require close monitoring by the
clinical team. Also, some ethical considerations can become obstacles to the
implementation of the remote trial model in pediatrics.

Plastic Surgery: obviously, any condition requiring surgery requires follow-up with
the healthcare institution of the practitioner who performs the surgery, especially to
prevent post-surgical complications. The remote trial model then becomes
practically not feasible in these cases.

Trauma (Emergency, Injury, Surgery): traumatic situations in the emergency room

by their definition involve the intervention of medical staff, thus eliminating any
possibility of the remote trial model.
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 Vaccines: again, by definition, clinical research examining the effectiveness of
vaccines requires the intervention of medical personnel to administer the vaccine,
eliminating the possibility of the remote trial model, but may be feasible by the
hybrid model.

It is important to note that for many of the therapeutic areas described above, while the
completely remote trial may not be suitable, the hybrid model can perfectly fit in some cases.
A thorough assessment is therefore recommended to identify opportunities where a hybrid
model may be suitable. All other therapeutic areas contain conditions that may apply the
remote trial model, especially when it is possible to measure the primary and secondary
outcomes of disease progression using mobile technology. This includes indications such as
diabetes, respiratory diseases and hypertension among others. Also, for some indications in
these therapeutic areas, clinical research often aims to improve patients quality of life, which
is often measured using validated questionnaires that can be administered by portable smart
technology (ePRO, BYOD). Such indications represent an excellent opportunity for the
implementation of the remote trial model.
Rare and orphan diseases also represent an excellent opportunity for the
implementation of the remote trial model, especially because of the scarcity of patients who
are affected. Patients of rare diseases are scattered over a wide geographical radius, and it is
not always easy to recruit in those studies. In addition, access to clinical trials of orphan
diseases becomes more difficult for patients who must travel long distances to participate. In
contrast, the mechanism of many orphan indications is naturally less well understood, thus
making clinical research protocols more complex. Also, the scarcity of these patients presents
a challenge to clinical research to obtain a sufficient sample size to generate significant results.
These obstacles may deter clinical researchers to apply the completely remote trial model for
orphan indications, but the hybrid model could be better suited, to significantly reduce the
travel burden on patients. Also in orphan indications where the measured outcome is the
improving of the quality of life through a validated instrument (questionnaire), the remote trial
model becomes much more interesting. It is therefore valuable to consider the remote trial
model and/or a hybrid model in the design of clinical trials for orphan indications. The
ultimate goal would be to improve access to clinical research for orphan indication patients, so

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the application of only some of the components of the remote trial model could help in
achieving this goal.
The clinical phase of the study is also important to consider in designing a remote trial.
It is known that Phase I involves research in healthy volunteers to determine the treatments
safety, a suitable non-toxic dose and potential side effects. Phase I is typically the first human
exposure to treatment, and thus involves a risk due to inexperience with the treatment at the
beginning of this phase. Phase I trials usually require interaction and monitoring of healthy
volunteers with clinical staff in a physical establishment for a specific period. The remote trial
model is therefore not easily applicable in Phase I.
Phase II clinical research is usually the first exposure of patients to treatment. It
generally aims to measure the effectiveness of the study drug for the first time in a group of
patients afflicted by the disease, while examining the toxicity of the treatment. In some cases,
the purpose of phase II is to study the effects of different doses of the treatment. In this phase,
the tolerable and toxic doses are known in healthy volunteers from Phase I, but the response to
treatment in patients is not. There is therefore a risk of toxicity that could be an obstacle to the
implementation of the remote trial model. However, the opportunity to apply the remote trial
model in Phase II is also present due to the limited sample size of Phase II compared to Phase
III, allowing sponsors better control of the trial. It is therefore important for the sponsor to
assess the risk to patients before deciding to go with the remote trial model in Phase II,
especially if the drug toxicity profile is not yet known in patients. Ultimately, Phase II may
represent a good opportunity for the remote trial model if the risk of treatment toxicity is not
considered high, especially due to a smaller sample size and a shorter duration compared to
Phase III.
Phase III is a pivotal clinical research phase and the most costly for sponsors. At this
stage, the aim is to confirm the efficacy of treatment, monitor adverse effects and assess the
study treatment compared to the standard of care on the market. A clinical program for an
investigational new drug may contain several Phase III studies to obtain marketing approval.
Under ideal conditions where drug toxicity of escalating doses and adverse effects related to
treatment are well known and they do not pose a fatal risk to patients, Phase III would be the
most appropriate phase to implement the remote or hybrid trial models. The remote trial model
in principle could reduce certain costs associated with research in Phase III, including study
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and site initiation costs. On the other hand, the multi-centric and international nature of Phase
III studies can be an assured challenge for the remote trial model, especially when considering
the legal aspect of patient data transfer across national borders. For this, we consider that the
remote trial model can be enabled in Phase III by establishing one coordinating site per world
region or country. Again, the unique laws of each country can become hindrances to its
application. Finally, the pivotal nature of Phase III studies may render sponsors more risk
averse and try to avoid the application of the remote trial model, preferring perhaps a more
conservative traditional model to reduce potential failure risks associated with piloting a new
model. In this case, starting with the hybrid model to gain experience in implementing the
remote trial components seems more fitting. Nonetheless, Phase III represents a reasonable
opportunity for the remote or hybrid trial models, especially if the therapeutic area, data
collection and a tolerable risk are favorable for its applicability.
Phase IV clinical research occurs after product commercialization, often to get more
information about long-term side effects or to study the response to treatment in specific
populations. At this stage, the drug is already marketed, its effectiveness already determined
for one or more indications and toxicity and adverse effects should already be known. Thus,
the risk for sponsors is considerably reduced compared to Phase III. Phase IV represents
therefore an ideal opportunity for the remote trial model, especially with the comprehensive
knowledge regarding the treatment at this stage. The opportunity is significantly higher in
Phase IV compared to all other phases of clinical research, and it is advisable for
pharmaceutical sponsors intending to apply the remote trial model for the first time to start in
Phase IV to gain more experience as to its applicability.
Another clinical consideration would be to examine the interventional or observational
nature of the clinical study. Phases I, II and III are generally interventional in nature, since
their purpose is to examine the effect of the intervention in relation to the progression of a
disease or condition. Phases IV or 0 (when research is done in an exploratory context prior to
Phase I) can both be interventional or observational depending on the study itself. The
observational context of clinical research is defined by the absence of a specific treatment in
the study, in the purpose of observing the progression of a condition or disease across the
population in the context of their everyday life. It is therefore clear that the observational
context is much more favorable than the interventional context for the design and
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implementation of a remote clinical study. Moreover, the observational context is much more
flexible from a regulatory perspective and considerably reduces risk for sponsors. Despite the
remote trial model being beneficial and applicable in both contexts, it is reasonable to
advocate the observational context for sponsors who want to apply the remote or hybrid trial
models for the first time. This is especially valid for sponsors who want to first gain more
experience in applying the various components of the remote trial model and make a gradual
transition of the model to clinical research in an interventional context.
Finally, another situation conducive to the implementation of the remote trial model
would be for clinical research in Animal Health. For pharmaceutical sponsors with a program
and a portfolio in Animal Health, piloting the remote trial model may seem to be ideal in this
area. Obviously, some components of the remote trial model are no longer valid for a clinical
study in Animal Health, such as the recruitment of subjects by dedicated social networks and
telemedicine, but remote data collection and remote monitoring can easily be conceived. Also,
clinical research in Animal Health can be an excellent opportunity for sponsors to absorb the
operational details related to the conduct of a remote trial, to eventually apply these lessons in
Human Pharma Health. Ironically, this example of the application of the remote trial model
resembles that of clinical research in Human Pharma Health, which is usually preceded by a
non-clinical research phase involving studying the molecule in animal models.

4.1.2 Regulatory, Ethical and Legal Considerations

At first glance, the remote trial model seems to be filled with obstacles at the
regulatory level. Skeptics might say that it is even impossible to obtain approval of regulatory
agencies for this type of trial. This perception seems to be rather more myth than reality,
because regulatory agencies remain open to innovative concepts to improve clinical research.
This was confirmed during our interaction with the FDA in the context of this research (86)
and during consultations with US and Canadian regulatory experts in the industry. For its part,
the FDA confirms the lack of experience of the pharmaceutical industry and the agency in this
area but supports the direction of the remote trial concept. In addition, in a recent Federal
Register docket, the agency solicited industry executives to provide input on the use and
barriers of implementing technologies and innovative methods to conduct clinical
investigations (57). This initiative from the FDA engages various actors involved in clinical

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research (industry, CRO, technology solution providers, etc...) to eventually form its own
opinion and potentially generate a guideline or recommendation. It therefore demonstrates the
proactive stance of the agency towards these innovative technologies, and decreases the effect
of critics negative perceptions about it. To date, there is still no guideline issued by any
regulatory agency (FDA or other) on the design and conduct of clinical research with the
remote trial model. A clear position of the agency would greatly assist the industry to act in
this direction and adopt more components of the remote trial model. Recently in 2015, CTTI,
an organization supported in part by the FDA, initiated a project to evaluate the concept of
"mobile clinical trials" (94), in order to generate best practices recommendations with regard
to this subject. The completion of this project by CTTI could solidify perceptions of observers
for the implementation of the remote trial model.
Shipping investigational drugs directly to patients in the study may also pose an
obstacle from a regulatory point of view, since it is required that a principal investigator
certified in clinical and medical practice to provide the investigational drug directly to
patients. This restriction may have to be lightened by regulatory authorities to facilitate the
execution of clinical research by the remote trial model. Alternatively, sponsors may also
request a waiver to that rule from the agency in the context of a remote trial pilot. Regulatory
agencies were open to this flexibility for Pfizers REMOTE trial (87) with the demonstration
of a robust clinical protocol and reasonable justification for the waiver. An alternative to
overcome this obstacle would be to partner up with local pharmacies that could ensure control
and proper dispensing of the study medication to study patients. This would allow easier
access for study patients to the study medication while placing responsibility of investigational
drug dispensing to qualified professionals (affiliated pharmacists). This partnership with local
pharmacies represents an interesting alternative for clinical supplies management and IND
dispensing for the implementation of the remote trial, but it potentially adds a new source of
costs with fees paid to affiliated pharmacies.
Another very important aspect from a regulatory perspective is the issue of integrity of
research by the remote clinical trial model. This starts with identity validation for patients, to
avoid fraud in clinical trial enrollment. Additionally, it is important to confirm that the
collected remote data are valid and generated by the enrolled patient in the trial, and not by
another individual. In addition, for regulatory agencies, it is important to demonstrate the
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robustness of the scientific evidence generated by clinical model, in terms of specificity,
sensitivity, reproducibility and clinical relevance. This would therefore require the validation
of wearable devices for medical grade to be used in the trial. Finally, matters pertaining to the
wellbeing of patients, the security of their data and respect for their privacy remain very
important from a regulatory and ethical perspective. It is therefore important to maintain
compliance with regulations such as HIPAA and the Canadian data privacy provincial laws in
the context of the remote trial model.
From an ethical point of view, the remote trial model involves a central IRB to review
the trial protocol before study startup. The geographical dispersion of patients in the remote
trial may raise questions about the validity of the central IRB, and its representation of patients
with whom it is not in direct contact. The argument cites that as the study takes place primarily
at a distance, the IRB cannot adequately represent patients without necessarily knowing the
specific context in which they participate in the study. This argument is however also valid for
the traditional clinical trial model where clinical research sponsors increasingly employ central
IRBs representing all study patients. FDA guidelines (58) regarding IRBs may therefore need
to be adapted to serve as a reference point for using central IRB services in the context of a
remote clinical trial. Other similar ethical considerations are also important to consider, such
as issues of patient data integrity, authenticity, security and privacy. Finally, the evolution of
the doctor-patient relationship through the remote trial model may also need to be reviewed
from an ethical clinical research standpoint.
The difference in legislation through the different states, provinces and territories could
also pose a challenge to the implementation of the remote trial model. Thus, a principal
investigator with a license to practice medicine in a state or province may not have the legal
license to practice in another. This raises a potential compliance issue of having a principal
investigator leading a trial remotely for patients that reside in a different state or province from
his. This consideration is also relevant regarding the shipping of investigated drugs across
provincial, territorial or state borders. As follows, there are current efforts in the US Senate to
break down these barriers through the various states in the United States (59). In Canada, there
is still no similar national initiative to overcome the existing obstacles for the adoption of
telemedicine to allow principal investigators to treat patients residing in other provinces (60).
In contrast, each Canadian province has guidelines for the adoption of telemedicine that
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describe the procedures for remote interaction between doctors and patients, as well as use
cases for telemedicine across provincial borders (60). The progress of these initiatives could
establish telemedicine as a valid option for clinical research with the remote trial model, by
eliminating legal barriers perceived to be a major obstacle to the development of the remote
trial model beyond national, provincial and state borders.

4.1.3 Technological Considerations

The proposed remote trial model heavily depends on recent technological advances.
The adoption of any new technology brings with it some challenges and considerations to
support its proper use. Technological considerations regarding the remote trial model fall into
three subgroups: considerations related to the genesis of data, considerations related to
computer hardware and connectivity, and considerations related to the implementation of the
remote trial.
The genesis of data is probably the most important pillar for the success of the remote
trial model in clinical research. The model not only promises to generate more data, but also to
improve the data quality in order to produce more robust clinical evidence. To support this
commitment, it is important to follow the principles of good documentation practices
(ALCOA - Attributable, Legible, Contemporaneous, Original and Accurate) (63, 84), to obtain
reliable data and trace its accountability back to the patient in the study. Thus, the technology
used to generate clinical data should be traceable to the specific study patient and not to any
other individual. Also, it is important to demonstrate the reproducibility of the study and
certify specificity of the data (the collected data is specific to the event we want to measure
and not something else) and sensitivity (the instrument that collects the data is responsive to
the event being measured and shows no breach in the collection) during data collection. These
aspects can all be confirmed by cooperating with medical and wearable device manufacturers
to validate their data collection methods for the study. Moreover, it is necessary to develop
algorithms that can analyze the huge amount of data obtained by continuous data collection.
The analytical capacity of current software is probably not at par with the volumes of data
generated and stored in the cloud. To determine the clinical relevance of these data, it will
therefore surely be essential to adapt and improve data analysis software platforms and
algorithms. Finally, in a world where data piracy takes a larger place in the fear of consumers,

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security and data privacy remain again extremely important to consider for the success of the
remote trial model. The increased dependency on the cloud for storage and transfer of data
poses a definite risk to data security and privacy. Improving security and data encryption
methods without restricting accessibility are thus essential to inspire confidence in this model.
Hardware and connectivity are two other important aspects to consider in
implementing the remote trial model. As previously noted in this work, one third of consumers
that have used a wearable device abandoned usage after 6 months (46). Battery life of these
devices must be improved to a level that can support a clinical study for its entire duration,
without needing to replace or recharge the battery. This would improve compliance with
constant wearing of the device and would limit reasons for removal by patients. The necessity
to consistently remove the device to recharge it also represents a risk for data collection within
the remote trial model. Moreover, seamless connectivity of wearables with their base (usually
a smartphone or a tablet) is necessary for their propagation and usefulness in clinical research.
All these factors affect the usability and ease of use of wearables, and any improvement in this
direction would favorably enhance the implementation of the remote trial model. Finally,
although smart device proliferation is increasing over the years, it is known that its market
penetration varies by age group. This means that one cannot assume that all patients will
necessarily possess a smartphone, especially elderly patients. The scale of this problem will
gradually decrease over the next years, especially when the millennials generation reaches old
age. However, in the immediate future, this issue will force sponsors to question the feasibility
of the remote trial model for disease conditions affecting elderly patients. The requirement of
having to provide smart devices as well as WiFi or LTE connectivity plans could also be a
deterrent to the adoption of the remote trial model, especially due to the added costs that this
would bring.
Speaking of costs, the early adoption of any new concept is usually associated with
additional costs while gaining experience and improving the concept. It is therefore
conceivable that the first few iterations of the remote trial model implementation might seem
to be more expensive than the traditional model on a short-term basis. However, as with any
innovative concept, the short term is typically filled with knowledge acquisition and
experience gain necessary to advance research breakthroughs. The benefits generated by the
acquisition of such knowledge may justify the increased short-term costs. In the long term, the
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expertise achieved by the implementation of the remote trial model and the advancement of
technology could help generate financial and operational savings in clinical research for the
pharmaceutical industry. Still, a thorough economic analysis will be required to demonstrate
the financial value of the remote trial model in the short and long terms.
Moreover, while still at a very immature stage, the components of the remote trial
model are spread across several different vendors. This wide spread leads to fragmentation in
the landscape and requires the establishment of integration standards and interoperability
between different solutions. Consolidating these solutions to one or two suppliers, and the
development of clear integration and interoperability standards, will facilitate the
implementation of the remote trial model. Finally, it will be important to demonstrate the
generalization of clinical research by this model, by ensuring the inclusion of different strata
of the population, not just tech-savvy individuals. It will be important to take this into account
in the design of any study by the remote trial model, to avoid introducing a selection bias in
the study population. All these technological considerations should thoroughly be examined
for the hoped success of the remote trial model.

4.1.4 Change Management Considerations for Clinical Operations

departments
Throughout this project, we have had several conversations with various actors
involved in clinical research across the industry. In this context, we talked to colleagues at BI
and other pharmaceutical companies, as well as executives from affiliated life-sciences
companies (CROs, suppliers, sites, etc...). Several of these conversations happened during
conferences relating to clinical research technologies (SCOPE 2014 (88), SCOPE 2015 (89),
SCOPE 2016 (90), NYAS Mobile Health Seminar 2015 (91), CBI Clinical Technologies
Congress 2016 (92), CHI Clinical Innovation Summit 2016 (93)). Moreover, the remote trial
concept described throughout this work was presented during some of these conferences (90,
92, 93), and was generally well received by attendees, and generated much interest and several
critical conversations on the topic.
During this journey through the exploration of the various components and the
development of the remote trial model concept, it gradually became clear that the main
adversity facing the implementation of the model is not of clinical, regulatory or technological
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nature. In contrast, it is rather the general culture of resistance to change in the pharmaceutical
industry, specifically within Clinical Operations units which happens to be the greatest
conceivable obstacle. Visibly, this resistance can be sourced from different arguments, such as
the path of innovation in the field of Clinical Operations must be slow, mainly due to the
perceived risk at the regulatory level. The typical argument, stating that the traditional clinical
research model is proven as the most adequate for the conduct of clinical trials, is commonly
invoked. Some skeptics even say that the clinical study in the absence of clinical sites cannot
be controlled properly. The well-known history of clinical research and strict regulation in this
area partly explain the reluctance of Clinical Operations departments to adopt new concepts
for the conduct of their business. The convenience of inertia for change and the increased
dependence on the multi-centric model involving several clinical sites may provide an
additional explanation for this resistance. Finally, part of the resistance may come from those
same clinical sites and CROs, since the remote trial model directly interferes with their
business models, and forces them to adapt.
In response to these concerns, it is necessary to refute the perceived threat to the
survival of clinical sites and CROs by the remote clinical trial model. It is clear that the remote
trial model always requires the involvement of a central coordinating clinical site. This site
will have more responsibilities and will probably have to adapt its functions, but will certainly
not be considered redundant. On the contrary, the success and proliferation of the remote trial
model will result in the ability to run more clinical trials by the pharmaceutical industry, thus
requiring more clinical sites and CROs services. Also, the remote trial model will not
completely replace the traditional model in clinical research, because, as previously discussed,
it is not applicable in all cases. It is rather anticipated that this model will complement the
traditional model instead of replacing it. This is also demonstrated by many other innovations
of the last century, such as email complementing traditional mail, and cellular phones
complementing the traditional phone.
Another important consideration for the pharmaceutical industry will be the necessary
evolution of several stakeholder roles in the development of the remote trial. For instance, the
Clinical Research Associate (CRA) role will surely have to adapt towards a more proactive
approach in managing the study and risk monitoring. With centralized risk-based monitoring,
CRAs will have access to more real-time information about the study, and will therefore focus
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on specific problems depending on their known risks. The common practice of full Source
Data Verification (SDV) will probably change depending on known risks. Other roles in
clinical research must also evolve in order to achieve success with the promise of the remote
trial model. The role of the principal investigator and clinical staff and that of the clinical trial
monitor may need to adapt. In addition, statistical analysis of clinical results may also have to
evolve based on the need to include huge amounts of data obtained during continuous remote
data collection using handheld smart devices. Cultural and organizational changes in all these
different clinical research stakeholder roles are one of the biggest challenges to overcome for
the implementation of the remote trial model. Pharmaceutical companies may need to adapt
their organizational structures to include teams specialized in the testing and implementation
of digital health technologies for clinical trials. Thus, the human side of change management
becomes one of the most important aspects to consider for the success of the remote trial
model.
Moreover, the application of an innovative concept generally takes several years before
materializing and it is clear that the remote model is not yet ready to suddenly disrupt all
Clinical Operations functions. The application of the remote trial model must rather be
through a gradual change to allow the solid gain of experience for its components. It is
therefore clear that the pharmaceutical industry requires change managers within their
organizations to promote a steady change of the operational and business culture in clinical
research, and lead to a more patient-centered approach.

4.2 Applying the model Case Study

Our case study revolves around a Phase IV clinical trial proposed at a large
pharmaceutical company in 2015, but was canceled due to budgetary prioritization (not
connected to the remote trial model). The referred study is a randomized, double-blind,
crossover clinical trial in the United States including 140 patients at 30 sites, to evaluate the
efficacy and safety of two compared treatments for COPD African-American and Hispanic
patients, after 6 weeks for each treatment. The primary endpoint is the assessment of
pulmonary function and strength (FEV1/FVC). Secondary endpoints are: basic and transition
dyspnea indices (BDI/TDI) (61) to measure the effectiveness of treatment on improving the
76
patient's breathing, the CAT (COPD Assessment Test) and SGRQ (St. George's Respiratory
Questionnaire) to measure patients perception in relation to the progression of their condition,
and a questionnaire to assess patient satisfaction during treatment. An initial screening period
is specified in the protocol, followed by two treatment periods (one per treatment) separated
by a washout period. Eight visits are planned in the protocol: two for the screening period, and
three for each of the two study periods. The study protocol anticipates the signing of the
informed consent documents at the screening visit, a complete medical examination, patient
training for the use of the inhaler and delivery of study drug and rescue medication to the
patient. The primary (FEV1/FVC) and secondary (BDI/TDI, CAT, SGRQ and patient
satisfaction questionnaires) parameters will be measured at the first and third visits of each
treatment period for the study, and at the last study visit. Telephone follow-ups will be done at
the second visit of each period to monitor adverse effects of the treatment, which will also be
followed for the duration of the study. Tables 3 and 4 show the complete synopsis of the study
and the procedures at each visit.

Table 3: Study Synopsis with all expected procedures per visit (Part I)

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Table 4: Study Synopsis with all expected procedures per visit (Part II)

The conversion of this study towards the remote model starts by replacing the 30
clinical sites by one central coordinator site. The selected site should ideally be recognized and
specialized as a leading institution in respiratory diseases, and must have within its ranks a
specialized clinician to act as a principal investigator for the study. The recruitment strategy
for the remote study involves using this central coordinating site, as well as the various
COPD-specific dedicated social networks described in earlier sections. Using additional
techniques for targeted patient recruitment through electronic medical records and platforms
such as TrialReach and CAVII can further assist in reaching enrollment goals across the
United States. The identified potential study patients can pass the preliminary screening at the
central coordinator site (if they live within reasonable proximity) or online via the study web
portal, to determine their general eligibility for the study. For patients residing far from the
central coordinator site, telephone contact will be established with site staff after the patient
decides to obtain more information about the study and to continue the screening process. At
the end of this contact with the site, the patient may decide to abandon the idea of participating
in the study or to continue. If he/she decides to continue, clinical study staff will mail him a
tablet loaded with the electronic informed consent mobile application. With that, the patient

78
also convenes to an appointment with study staff for revising the electronic informed consent
form on the tablet. The patient agrees to read through the electronic informed consent form
briefly before this appointment, and records any questions and unfamiliar terms from the
document for discussion with the principal investigator of the study. The signing of the
electronic consent form is only done after the audio-visual or physical interaction at the site
between the principal investigator and the patient, during which the patient can ask any
questions about the study and get all the necessary information before consenting to
participate in the study. The patient and investigator sign the document at the same date and
signatures are duly registered in the electronic informed consent form. Alternatively, a clinical
staff representative can go to the patient's home to complete the signature of informed consent
electronically, as well as perform all the necessary procedures for the preliminary screening
visit. When the patient is enrolled in the study, all medical and physical examinations can be
done at the central coordinator site, an affiliated clinic in geographical proximity from the
patients residence or through a GCP-certified medical practitioner (doctor or nurse) from the
comfort of the patients home. All expected medical procedures to determine the patient's
baseline will be performed by the certified medical practitioner. An adequate patient training
for the use of the inhaler will also be provided and documented at this visit. The patient will
also receive during this visit the necessary instructions for the rescue medication, as well as all
necessary devices for the study, such as the smart spirometer synchronized with a smart device
platform and heart rate measuring devices to determine the patient's ECG and vital signs.
Instructions will also be provided to download and register the mobile application for
obtaining patient reported outcomes through the various questionnaires of the study (CAT,
SGRQ and patient satisfaction). This application will also serve as a patient engagement tool
throughout the course of the study. Another secondary endpoint is added to the protocol of the
remote study: the impact of the treatment on activity levels and sleep patterns of the patient,
which will be measured using a wearable activity monitoring device. This device as well as
usage instructions will also be provided to the patient at this initial screening visit. In addition,
the patient will provide his first measurement for respiratory strength (FEV1/FVC) using the
provided spirometer, which will process the data through the cloud to the clinical database.
Throughout the study period, patients are instructed to use the spirometer once daily in the
morning to record measurements for the pulmonary function test. During the fourteen days
79
between this initial visit and the patient's treatment randomization for the first study period,
the protocol requires daily measurements of respiratory strength, which will help in getting a
more accurate baseline for the patient. In addition, the inhaler is uniquely assigned and
identified in the database for each patient and is equipped with an activation sensor which
records its usage and uploads it through the cloud, thus verifying treatment adherence for each
patient of the study. Five days before the start of treatment, the patient will be randomized to
one of two study treatments by IVRS (Interactive Voice Response System). Site staff from the
central coordinator site will ship the study treatment of the first period directly to the patient's
home or to an affiliated pharmacy close to the patients home. Day zero of the study is the day
the patient receives the medication in hand, and starts inhaling the study medication through
the inhaler. The study treatment must be taken once a day during the course of the study.
Alternatively, at day zero, a nurse will go to the patient's home to initiate the first protocol
visit. The three planned visits in the study protocol for each period will be different for the
remote trial with electronic visits through a telemedicine platform with an interaction between
the principal investigator and the patient.

The telemedicine e-visits will be conducted with a specialized platform where patient
and investigator can interact through an audiovisual contact. At the time specified by the
appointment of the e-visit, the principal investigator initiates an audiovisual call through the
telemedicine platform, and will start the protocol provided for the e-visit. Vital signs will be
measured using the devices provided to the patient, which are also connected to the mobile
telemedicine platform. Thus, the principal investigator shall advise the patient to use the
sphygmomanometer for example to measure his/her blood pressure. The device is
synchronized directly with the mobile telemedicine platform and records vital signs measured
instantaneously, under the supervision of the principal investigator. The first visit could also
alternatively be done in parallel with the physical presence of a nurse at the patient's home and
the principal investigator remotely via the telemedicine platform. The nurse takes the
responsibility of training the patient in the use of the inhaler and the spirometer as well as
performing any necessary physical procedure at this first visit. The principal investigator
checks the patients vital signs, records pulmonary strength test measurements from the
spirometer and oversees the BDI/TDI questionnaire to assess dyspnea indices for the patient.

80
The BDI/TDI questionnaire must be administered by the principal investigator according to
the protocol, and therefore cannot for example be independently completed by the patient from
his/her smart device. The CAT and SGRQ questionnaires as well as the patient satisfaction
survey will be administered through a mobile application, and must be completed weekly by
the patient. The patient's daily activity levels will also be captured by the activity monitor
wearable device and uploaded daily to the cloud. The second visit of the first treatment period
will also be conducted through telemedicine, where patients will report all adverse events that
they may have experienced. The third visit of this period will be identical to the first, except
without the need of a nurse at the patient's home. A washout period of 3 weeks is expected
between the two treatment periods. The second treatment period starts thereafter, and will be
identical to the first period, with the exception that the treatment is different. The last visit of
the second treatment period will conclude when the patient hands back the inhaler and any
other medication to the study team. The study formally ends after this visit. A follow-up is
done with the patient 3 weeks after the end of the study to capture and report any other adverse
events that may have occurred post-study.

During the entire duration of the study, close monitoring is achieved by scrutinizing
and validating all study data collection. Treatment adherence is also monitored by the recorded
daily activation of the inhaler. Additionally, all adverse events will be closely monitored
throughout the study by the sponsor and the central coordinator site. The synopsis of the
converted clinical trial from the traditional model to the remote model is described below in
Tables 5 and 6, with the changes marked in red.

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Table 5: Study synopsis by the remote trial model with planned activities for each visit (Part I)

Table 6: Study synopsis by the remote trial model with planned activities for each visit (Part II)

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 4.2.1 Economic Impact of the Remote Trial Model

In order to determine the economic impact of the remote trial model in clinical
research, it is necessary to identify and classify the several clinical research costs in different
groups. As part of this work, we cite a recent publication that analyzes the various costs
related to clinical research. This publication was produced in 2014 by the Eastern Research
Group (62), which submitted their research paper on the economic impact of clinical trial
conduct, for the United States Department of Health and Human Services (DHHS). As part of
their work, they estimated clinical research costs by phase for each cost category. Table 7 is
extracted directly from this paper (62).

Table 7: Analysis of the different clinical research costs, per phase of clinical research.

Extracted from Examination of Clinical Trial Costs and Barriers for Drug Development, by Sertkaya et al. (66), Eastern
Research Group, 2014 (Table 2, page 33 of the original document, section 3 p. 6).

Table 7 provides a cost estimate for each clinical research category for each phase, and
provides the estimated proportion that these costs represent compared to the total costs of the

83
study. The last two categories are estimated relative to the calculated subtotal. The category
"Site Overhead" is estimated to be between 20% to 27% of the calculated subtotal costs. The
authors believe that the sum of the calculated subtotal per phase and the "Site Overhead" cost
category accounts to 70% of total costs in clinical research. The last portion of 30% is
categorized as "All Other Costs" and includes all additional costs for sponsors to run the study
and other costs not captured anywhere. Our analysis of the impact of the remote trial model on
clinical research costs takes the Phase IV study described earlier in this chapter, and proposes
an estimate of how the costs will adapt upwards or downwards based on the differences
between the traditional and remote trial models. The analysis is based on the costs column for
Phase IV clinical research described by Sertkaya et al. (62) and is described in Table 8 below.

84
Table 8: Analysis and comparison of the costs, productivity and patient convenience between the
traditional and remote clinical trial models, for the Phase IV study described earlier.

Before embarking on the discussion of the above table, it is important to state that the
analysis of the economic impact is limited by its theoretical nature, in the absence of an actual
case study implementation of the remote trial model. The purpose of this analysis is primarily
to get an idea of the total costs that affect clinical research, and to attempt to predict the
85
potential impact of the remote trial model for each cost category. For this analysis, we hope to
predict the full impact of the remote clinical trial model on the following three aspects: total
costs, efficiency (which may also translate into costs) and convenience to patients. With this
comprehensive analysis, we can attempt to judge whether the remote trial model is worth
implementing in the short and long terms from an economic point of view for pharmaceutical
sponsors.

The cost analysis of the Phase IV study described in Table 8 determines that the
majority of savings brought by the remote trial model come by reducing clinical sites, which
accounts for over 60% of the subtotal. This translates to a significant cost reduction for the
Phase IV study. However, it is important to consider that some cost categories end up being
higher with the remote trial model, including data management costs, patient retention costs
and honoraria paid to the principal investigator and central coordinator site. It is anticipated
that the increase in these costs would be significant (probably double or triple), but they are in
categories representing barely 6.59% of the estimated subtotal costs, so the total impact may
not be that significant. Hence, at first glance, the remote trial model may seem to represent
cost savings for clinical research, especially with the elimination of the multi-centric approach
and the costs associated with the multiple clinical sites. In contrast, our analysis reveals that
the "All Other Costs" category, which represents a 30% portion of the total costs, will be
increased for the remote trial model. This is due to the introduction of several changes in the
remote trial model from the traditional model, which naturally will have the effect of incurring
additional costs for the study conduct, while study teams adapt their processes to this new
approach. Moreover, it is conceivable that the remote trial model may require a more thorough
data analysis strategy when interpreting generated results to determine their clinical relevance.
It is also possible that regulatory agencies would require more information in the regulatory
dossier, due to the availability of more data for the course of the study. These factors all point
to a potential increase in the "All other costs category. Finally, the implementation of the
remote trial model components obviously result in higher costs compared to the traditional
model. This is mainly due to service costs for the implementation of several new technology
platforms, which is not the case for the traditional model. These costs may be absorbed by
other departments inside the pharmaceutical organization, such as IT or Clinical Data

86
Management departments, but they will result in additional short term costs for the sponsor.
Thus, under the current clinical budgeting approach where budgets are planned per trial, the
addition of these platforms for a single study may seem to significantly increase the cost of
clinical research compared to the traditional model. In addition, some sponsors might opt for
the hybrid model to start, which does not completely eliminate clinical sites and their
associated overhead costs, while still adding the implementation costs for one or a few
components of the remote trial model, which would therefore lead to higher costs. However, a
shift in the budgetary strategy allowing an investment on the entire clinical research portfolio
may help in reducing per study costs for the implementation of the remote trial components.
This comprehensive strategy would hypothetically decrease costs by allowing these new
platforms to be used across the clinical research continuum, and prevent the duplication of
efforts by reusing these platforms across all clinical studies in the sponsors clinical program.
Therefore, it is reasonable to argue that the remote trial model will not reduce clinical research
costs on a short-term basis for a pilot study, since these costs are perceived to be increased
when considered for a single study. In contrast, the long-term vision suggests that the total
cost of clinical research in the pharmaceutical industry could be reduced with the remote trial
model, especially after the maturity of its components in the technological landscape when
globally implemented across the sponsors clinical program. Furthermore, our analysis shows
that productivity gains are theoretically anticipated in the majority of the described categories,
especially for categories affected by the components of the remote trial model, which would
likely lead to potentially shorter and more robust studies. A more detailed analysis, outside the
scope of this work, may be required to translate these productivity gains in monetary savings
in order to have a more accurate representation of the economic impact of the remote trial
model. Finally, where applicable, it is anticipated that patient convenience would be much
improved by the remote trial model, contributing thus to an improved perception of patients
for clinical research and the pharmaceutical industry in general. It is difficult to quantify the
impact of this improved perception of patients, but it is conceivable that this would lead to
better patient engagement in clinical research and therefore potentially lead to additional
gains. Moreover, this enhancement in patient convenience is directly aligned with the modern
patient centricity vision for clinical research, and brings the industry closer to its goal of being
more patient-centric. Finally, in the absence of a concrete case study for the implementation of
87
the remote trial model in comparison to a similar study for the traditional model, our analysis
of the economic impact remains limited. Further analysis would be needed to get a more
accurate depiction of the economic impact of the remote trial model, with a real case
implementation comparing the two models.

4.3 Perspectives in Remote Clinical Trial Conduct within the

industry
As mentioned earlier in this work, one of the largest barriers to the adoption of the
remote trial model remains the general risk aversive culture in the pharmaceutical industry,
specifically in Clinical Operations. This prevalent culture in Clinical Operations stifles the
development of innovative concepts in clinical research, such as the remote trial model
described in this work. Thus, a necessary gradual culture change represents a large slice of the
efforts needed to advance the concepts of the remote trial model.
We considered it important to draw the perspectives of different stakeholders in
clinical research to the proposed remote trial model. To this end, we implemented a survey
containing 22 questions (see Appendix II) that addresses the components of the remote trial
model and perspectives of the model from different professionals involved in clinical research.
The survey was sent to executives of the following domains: academic and clinical sites,
clinical research organizations (CRO), pharmaceutical industry and technology providers to
the pharmaceutical industry. The survey contains three parts: the first includes questions on
respondents perceptions of each component on the remote trial model using a scale of 1 to 10
(10 = strongly agree, 1 = strongly disagree), the second includes perspectives on the various
obstacles related to the implementation of these components, and the third includes questions
on respondents perceptions on the implementation of the remote trial model and its current
challenges. The survey was made possible through the SurveyMonkey platform, and was
started in February 2016. The survey results are presented above in two parts, in Table 9.

88
Assumption that 10, 9 = High Supporters - 8, 7, 6 = Moderate Supporters - 5, 4, 3, 2, 1 = Skeptics
Pharmaceutical Industry
High Supporters Moderate Supporters Skeptics % High Supporters %Moderate Supporters %Supporters #Questions #Respondants
Patient Recuitment & Retention Component
32 35 5 44.44% 48.61% 93.06% 3 24
(Questions 1, 2, 3)
eConsent from clinic
24 23 1 50.00% 47.92% 97.92% 2 24
(Questions 4, 5)
eConsent from patient's home
6 13 5 25.00% 54.17% 79.17% 1 24
(Question 6)
eSource, ePRO, BYOD, wearables
46 40 8 47.92% 41.67% 89.58% 4 24
(Questions 7, 8, 9, 10)
Telemedicine
9 13 2 37.50% 54.17% 91.67% 1 24
(Question 11)
Remote Drug Adherence
6 14 4 25.00% 58.33% 83.33% 1 24
(Question 12)
Remote Trial Concept
13 10 0 56.52% 43.48% 100.00% 1 23
(Question 18)

Biggest 2 pain points for clinical trials: Patient Recruitment Non Patient-Centric Trials
Biggest Challenge to Remote Trial: Pharma Industry and Clinical Operations Culture isn't there yet (63%)
Earliest Interventional Remote Clinical Trial 2020-2035 (96%)

Assumption that 10, 9 = High Supporters - 8, 7, 6 = Moderate Supporters - 5, 4, 3, 2, 1 = Skeptics

Others (CRO, Academic, Sites)
High Supporters Moderate Supporters Skeptics % High Supporters %Moderate Supporters %Supporters #Questions #Respondants
Patient Recuitment & Retention Component
26 15 4 57.78% 33.33% 91.11% 3 15
(Questions 1, 2, 3)
eConsent from clinic
15 12 3 50.00% 40.00% 90.00% 2 15
(Questions 4, 5)
eConsent from patient's home
5 6 4 33.33% 40.00% 73.33% 1 15
(Question 6)
eSource, ePRO, BYOD, wearables
30 23 7 50.00% 38.33% 88.33% 4 15
(Questions 7, 8, 9, 10)
Telemedicine
8 5 2 53.33% 33.33% 86.67% 1 15
(Question 11)
Remote Drug Adherence
7 6 2 46.67% 40.00% 86.67% 1 15
(Question 12)
Remote Trial Concept
5 7 3 33.33% 46.67% 80.00% 1 15
(Question 18)

Biggest 2 pain points for clinical trials: Patient Recruitment Inefficient Data Capture methods
Biggest Challenge to Remote Trial: Pharma Industry and Clinical Operations Culture isn't there yet (60%)
Earliest Interventional Remote Clinical Trial 2020-2035 (86%)

Table 9: Analysis of the perspectives of different stakeholders in clinical research towards the
implementation of the remote trial components and the remote trial model.

At the top, answers from the pharmaceutical industry respondents. At the bottom, all other respondents.

As shown in Table 9, the majority of respondents, a proportion of 64%, comes from the
pharmaceutical industry. The purpose of the survey is to understand the acceptance level of
the remote trial model, especially among decision-makers in the pharmaceutical industry. To
do this, the results of survey respondents are classified into three groups: early adopters that
are strongly in favor of the remote trial model (respondents that strongly agree, with a
response of 9 or 10), the moderate adopters (respondents that moderately agree, with a 6, 7 or
8 response) and skeptics (respondents which gave a response equal to or less than 5).
According to the analysis, it is clear that certain components of the remote trial model hold a
good proportion (~ 50%) of early adopters, like patient recruitment and retention techniques,
e-consent made at the clinical site and electronic data capture at the source through smart and
wearable devices. The techniques described for remote monitoring (telemedicine, adherence to

89
treatment) seem to have a lesser proportion of early adopters (38% and 25% respectively),
which may indicate that the feasibility of these components is currently viewed unfavorably.
Another possible explanation is that these components represent a secondary priority for the
pharmaceutical industry at the moment. Remote electronic informed consent also does not
seem to be very popular, with only 25% of respondents being classified as early adopters,
indicating that the industry prefers to control the electronic informed consent process at the
clinical site before thinking to do it remotely. Also, it may indicate that some respondents
remain cautious to maintain the physical interaction between the patient and clinical staff
during the informed consent process. Interestingly, over half of respondents (57%) say that
they are strongly in favor of the implementation of the remote trial model in clinical research.
Moreover, if we also consider further respondents who are classified as moderate adopters
with the individual components of the remote trial model (Questions 1 to 12) or moderate
adopters of the integral remote trial model (Question 18), we observe that the resulting
proportion exceeds 90% for most components (with the exception of electronic informed
consent from the patients home which holds 79% agreement and remote treatment adherence
measurements which holds 83% agreement). This trend indicates that most of the
pharmaceutical industry respondents have a favorable perception of the remote trial model,
despite the risk-aversive nature of the business culture in the industry. This therefore promises
a plausible first step for the future of the remote trial model feasibility, especially considering
that the majority of respondents in the industry are in favor. The vast majority (96%) of
respondents believe that the remote trial model will be implemented in an interventional
clinical study in the period of 2020-2035, which is not so distant after all. Finally, over half of
industry respondents (64%) maintain that the biggest hurdle for the feasibility of the remote
trial model remains the need for cultural change in the industry and specifically in the field of
clinical operations.
Results are slightly different for all other respondents (not from the pharmaceutical
industry). We observe similar trends with respondents from the pharmaceutical industry for
the three most popular categories (patient recruitment techniques, electronic informed consent
from the clinical site and electronic data capture at the source and through smart and wearable
devices). This gives us an indication that all stakeholders in clinical research have a certain
consensus in these categories, and it seems that the priority in the near future will be to
90
improve clinical research in these categories. Electronic informed consent from the patient's
home remains a less attractive option for those respondents, with only a third of respondents
who are strongly in favor, similar to trends in industry respondents. This probably indicates
the same level of caution at the electronic informed consent level, with a clear preference to
master the concept at the clinical sites before taking it remote. Also, it may indicate that these
respondents prefer to maintain the direct interaction between clinical staff and patients during
the informed consent process. An interesting finding is noted for telemedicine and remote drug
adherence monitoring, with a greater proportion of respondents strongly in favor compared to
respondents from the industry. This trend may indicate that these respondents view a greater
importance for using technology in clinical research, despite the reluctance of the industry in
these categories. Another conclusion of this disparity could be the fact that the two different
classes of respondents (industry, non-industry) are not entirely in agreement about the priority
of these two categories (telemedicine, remote drug adherence monitoring), potentially because
some of the respondents have an interest in implementing those solutions for the industry. In
short, it is clear that industry respondents perceptions have a greater impact on the feasibility
of these two categories in clinical research than non-industry respondents, and technology
vendors must do more to bring these technologies to fruition in clinical research. Finally, it is
very interesting that the non-industry respondents perceive the remote trial model less
positively than respondents from the industry, perhaps indicating a reluctance to adapt their
business model or a fear of revenue losses by the introduction of the remote trial model.
Finally, insights gained through this survey correspond to the perceptions of
stakeholders in the pharmaceutical industry in general compared to the remote trial model. It is
important to note that a greater sample size may be required to provide more robust insights
for this survey. It is however clear that there is still much work to do for industry executives
and their non-industry partners to bring this concept to reality and to reap the benefits
promised by the implementation of the remote trial model. Improving clinical research
techniques and methods, remain however a priority for the pharmaceutical industry to better
achieve the goal of producing valuable therapies improving the health of millions of patients
who depend on them, and to proactively become more patient-centric.

91
 5. Conclusion
The pharmaceutical industry is pressed by external trends that require it to reconsider
its approach, and give rise to the concept of patient centricity. The technological advancement
brought by social networks, smart devices and remote monitoring opens new doors to the
pharmaceutical industry to reconsider the clinical research model and try to solve some known
problems connected to it. Typically, clinical research for the discovery and validation of new
therapies often use data collection on paper with a later transcription of this data to an
informatics system and is therefore totally dependent on clinical research sites. These
techniques often require great validation and quality assurance efforts to insure data integrity
and are therefore not well aligned with the technological capabilities of the current era. Also,
patients are often not very well engaged in clinical research, leading to issues with patient
retention in clinical research, which remains a considerable challenge for the successful
conduct of clinical studies. Several efforts are expended to overcome these challenges,
including the development of the remote trial model for clinical research conduct. The
application of the remote trial model in clinical research requires the consideration of a
number of practical factors, ranging from clinical, technological, legal and regulatory. In
addition, operational business culture in the pharmaceutical industry and especially in clinical
operations departments must adopt an attitude more inclined towards innovation and more
focused on the patient. These considerations do not come without struggles, as serious efforts
are needed on the part of multidisciplinary teams to get to the implementation of an innovative
concept such as the remote clinical trial model. However, it is necessary to understand that
innovation in the pharmaceutical sector takes time to settle and it is unreasonable to expect a
rapid change towards the implementation of the remote trial model. In contrast, it is rather
better to realize the promise of this innovation with small productivity gains by applying and
understanding some components of the remote trial model through isolated pilot studies. This
will lead to a gradual experience gain in their implementation, and establish progressive
confidence in these components, slowly but surely leading to the possible execution of the
remote trial model for clinical research conduct. In the short term, the remote trial model does
not promise a significant reduction in clinical research costs, but rather a gradual learning
towards better outcomes. In the long run, productivity gains and maturity of the different

92
processes and technology could lead to significant reductions in clinical research costs.
Perceptions of the remote trial model and its components are generally positive for the various
stakeholders in clinical research, for executives from the pharmaceutical industry and
professionals from CROs, academic institutions or technology vendors. In perspective, it is
reasonable to believe that the remote trial model will see the day as part of an interventional
study (phase I, II or III) within a twenty years period from today. By then, the rapid increase in
efficiency of technology will undoubtedly encourage the industry towards a gradual adoption
of the components of the remote trial model, hoping to improve the clinical research process to
promote the discovery of new therapies and meet the medical needs of the modern era.
Finally, the adoption of the remote trial model certainly does not replace the traditional model
of clinical research, but will certainly support the transformation of the pharmaceutical
industry towards a more patient-centered approach, and possibly contribute to the
improvement of clinical research.

93
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Annexes

Annex I: List of Therapeutic Areas

The list of therapeutic areas was cited directly from the CenterWatch organizations
website (https://www.centerwatch.com/clinical-trials/listings/therapeutic-description.aspx).
According to our analysis, 20 of the 31 listed therapeutic areas contain indications that can suit
the remote trial model in clinical research. In the following list, therapeutic areas marked in
green contain indications deemed suitable for the remote trial model, while those marked in
red are not suitable for the remote trial model.

Cardiology/Vascular Diseases

Dental and Oral Health

Dermatology

Endocrinology

Family Medicine

Gastroenterology

Genetic Disease

Healthy Volunteers

Hematology

Hepatology (Liver, Pancreatic, Gall Bladder)

Immunology

Infections and Infectious Diseases

Musculoskeletal

Nephrology

Neurology

Nutrition and Weight Loss

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 Obstetrics/Gynecology

Oncology

Ophthalmology

Otolaryngology (Ear, Nose, Throat)

Pediatrics/Neonatology

Plastic Surgery

Pharmacology/Toxicology

Podiatry

Psychiatry/Psychology

Pulmonary/Respiratory Diseases

Rheumatology

Sleep

Trauma (Emergency, Injury, Surgery)

Urology

Vaccines

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Annex II: Survey on the perceptions around the Remote Clinical
Trial model

Perspectives in Remote Clinical Trial Conduct

INTRODUCTION

Thank you for taking the time to complete the following survey. In the context of my
academic research with the University of Montreal, I am gathering qualitative data from
industry experts to better understand how clinical trial conduct can be automated in order to
improve efficiencies. We will ask for your opinion on various aspects of clinical trial
automation. None of the questions will identify who you are and none of the questions will
compromise your confidentiality agreement you have signed with your employer.

SURVEY COMPLETION INSTRUCTIONS

For each of the attributes outlined, you are instructed to rate on an analogue scale from 1 to
10 your overall opinion. Please indicate clearly with a check mark in the circle provided your
level of agreement with the statement.

Example:

Clinical trials can be further improved by integrating remote technologies?

Strongly disagree Strongly agree

1 2 3 4 5 6 7 8 9 10

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1. Would you or your organization use specialized social networks to identify and
recruit clinical study participants?

1 2 3 4 5 6 7 8 9 10

2. Would you or your organization use Electronic Health Records (EHR) data as a
source to identify and recruit clinical study participants?

1 2 3 4 5 6 7 8 9 10

3. Would you or your organization utilize digital outreach platforms such as TrialReach
or CAVII, to identify study participants?

1 2 3 4 5 6 7 8 9 10

4. Current paper based informed consent procedures used at the clinical trial site are
the most efficient method to obtain consent?

1 2 3 4 5 6 7 8 9 10

5. Would you or your organization use electronic informed consent procedures at the
clinical site to consent participants in a clinical trial?

1 2 3 4 5 6 7 8 9 10

104
6. Would you or your organization use electronic informed consent remotely (outside
the clinic from the patients home) to obtain consent to participate in a clinical
study?

1 2 3 4 5 6 7 8 9 10

7. Would you or your organization utilize e-Source to improve data collection methods
in clinical research?

1 2 3 4 5 6 7 8 9 10

8. Would you or your organization use electronic methods for collecting patient
reported outcomes (PROs)?

1 2 3 4 5 6 7 8 9 10

9. Would you or your organization allow patient reported outcomes collection using a
patients own device (BYOD)?

1 2 3 4 5 6 7 8 9 10

10. Would you or your organization allow patients enrolled in a clinical study to provide
biometric data from wearable devices?

1 2 3 4 5 6 7 8 9 10

105
11. Would you or your organization include telemedicine as an alternative to clinical
site visits during a clinical study?

1 2 3 4 5 6 7 8 9 10

12. Would you or your organization use an automated pill dispensing technology (e.g.
smart pill bottle) to track medication adherence and drug reconciliation?

1 2 3 4 5 6 7 8 9 10

13. In your opinion, what is the main pain point in running clinical trials in your
organization?

1. Patient Recruitment
2. Patient Retention
3. Informed Consent issues
4. Inefficient Data Capture methods
5. Inadequate Monitoring
6. Treatment Adherence
7. Non-Patient Centric trials
8. Other (please specify): ___________________________________

14. In recruiting patients for clinical trials, what is the most important factor for success
in your opinion (Choose one)?

1. Bringing more traffic to study website

2. Screening more patients for trial (increasing volume)
3. Consenting more patients
4. Better targeting of potential patients
5. Better engaging patients during trial and better retention after they've enrolled
6. Other (please specify):_______________________________________

106
15. What is the biggest challenge currently in obtaining informed consent for clinical
research?

1. Confirming patient understanding of trial

2. Length and complexity of informed consent process
3. Re-consenting subjects after amendments
4. Version tracking of consent documents
5. Other (please specify):_______________________________________

16. What is biggest challenge today with current data collection methods for clinical
research?
1. Clinical setting bias
2. Fragmented data collection
3. Data transcription from paper to EDC (not e-Source)
4. Not aligned with technological capabilities
5. No challenges
6. Other (please specify):______________________________________

17. What is the biggest challenge in current clinical trial monitoring efforts (without the
utilization of Risk Based and Remote Monitoring techniques)?

1. Full SDV is time consuming and ineffective

2. Reactive, not Proactive
3. Costly
4. No proven alternatives
5. Other (please specify):____________________________________

17-a) The Remote Patient-Centric Clinical Trial utilizes digital recruitment methods,
electronic informed consent, remote data collection methods from the patient's home,
remote monitoring, remote adherence monitoring and telemedicine. It reduces the
need to clinical site visits and allows patients to participate from home. Would you or
your organization consider using the Remote Patient-Centric Clinical Trial model for
running clinical trials in the future?

1 2 3 4 5 6 7 8 9 10

107
18. Overall, which of the following considerations are valid challenges for running a
remote clinical trial?

1. Guidance from Regulatory Agencies

2. Local and Federal legislations with regards to remote clinical research (shipment of
INDs across states, health consultation across states, etc)
3. Ethical and IRB considerations and buy-in
4. Interventional vs Observational setting
5. Other (please specify):____________________________________

19. What is the major challenge in the implementation of a remote clinical trial
(without sites, or considerable reduction of sites)?

1. Technology isn't there yet

2. Culture isn't there yet
3. Risks of data inaccuracy
4. Regulatory considerations
5. Model is not cost-sustainable yet
6. Other (please specify):____________________________________

20. What timeframe do you think would be the earliest time when the pharmaceutical
industry will launch its very first interventional / registrational remote clinical trial?
1. 2020-2035
2. 2035-2050
3. 2050-2099
4. 22nd century
5. Never

21. Which of the following best matches your domain?

1. Academic Institution
2. Clinical Research Organization
3. Healthcare Institution (Clinical Site)
4. Pharmaceutical Industry
5. Service Provider for Pharma
6. Other: Please specify _______________________________

108