Expert Opinion on Drug Safety

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A review of existing and emerging digital

technologies to combat the global trade in fake
medicines

Tim K. Mackey & Gaurvika Nayyar

To cite this article: Tim K. Mackey & Gaurvika Nayyar (2017) A review of existing and emerging
digital technologies to combat the global trade in fake medicines, Expert Opinion on Drug Safety,
16:5, 587-602, DOI: 10.1080/14740338.2017.1313227

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EXPERT OPINION ON DRUG SAFETY, 2017
VOL. 16, NO. 5, 587–602
https://doi.org/10.1080/14740338.2017.1313227

REVIEW

A review of existing and emerging digital technologies to combat the global trade
in fake medicines
a,b,c
Tim K. Mackey and Gaurvika Nayyarb
a
Department of Anesthesiology, University of California San Diego School of Medicine, San Diego, USA; bGlobal Health Policy Institute, San Diego;
c
Department of Medicine, Division of Global Public Health, University of California San Diego School of Medicine, San Diego, USA

ABSTRACT ARTICLE HISTORY

Introduction: The globalization of the pharmaceutical supply chain has introduced new challenges, Received 1 February 2017
chief among them, fighting the international criminal trade in fake medicines. As the manufacture, Accepted 27 March 2017
supply, and distribution of drugs becomes more complex, so does the need for innovative technology- KEYWORDS
based solutions to protect patients globally. Fake medicines; counterfeit
Areas covered: We conducted a multidisciplinary review of the science/health, information technology, medicines; substandard
computer science, and general academic literature with the aim of identifying cutting-edge existing and medicines; falsified
emerging ‘digital’ solutions to combat fake medicines. Our review identified five distinct categories of medicines; health
technology including mobile, radio frequency identification, advanced computational methods, online technology; anti-counterfeit;
verification, and blockchain technology. online pharmacies; supply
Expert opinion: Digital fake medicine solutions are unifying platforms that integrate different types of chain
anti-counterfeiting technologies as complementary solutions, improve information sharing and data
collection, and are designed to overcome existing barriers of adoption and implementation. Investment
in this next generation technology is essential to ensure the future security and integrity of the global
drug supply chain.

1. Introduction value of pharmaceutical brands, decrease economic output for

communities impacted, contribute to the growing global
1.1. Global trade in falsified and substandard medicine
threat of drug resistance, and have also resulted in documen-
The public health and patient safety threat of ‘fake’ medicines ted patient deaths [1,4,9,12,14–18]. From a population health
is a problem that has plagued the international community for perspective, failing to address the deleterious impact of fake
decades [1–3]. As early as 1988, the United Nation’s specialized medicines can severely jeopardize progress and billions of
international health agency – the World Health Organization dollars invested in development assistance for health, often
(WHO) – recognized the urgent need to develop programs to delivered through large-scale international aid programs
detect and prevent the import, export, and smuggling of a aimed at ensuring equitable, safe, and life-saving access to
host of dangerous medicines, including those categorized as essential medicines [12,19–21].
substandard, falsely labeled, unapproved, counterfeit, and fal- Reflecting the enormous scope of the problem, close to
sified (see Table 1 for definitions) [4–7]. Close to 30 years later, 1000 different medical products have been reported as
the global trade in fake medicines (which WHO recently lim- falsified or substandard to the WHO alone, including med-
ited to the terms ‘falsified’ and ‘substandard’) continues to be icines across all major therapeutic categories and those that
robust [8]. Varying estimates indicate that millions are poten- are both generic and branded/innovator products [10].
tially at risk from this form of globalized pharmaceutical crime Additionally, a study that analyzed data collated by the
that has matured into a multibillion-dollar industry endanger- Pharmaceutical Security Institute (a nonprofit, membership
ing patients in high and low-income countries alike [9–11]. organization of pharmaceutical company security directors)
The dangers posed by falsified and substandard medicines from 2009 to 2011, found that there were over 1500 fake
have been detected throughout the global drug supply chain medicine incidents reported in the ‘legitimate’ supply chain
including in brick and mortar pharmacies, healthcare facilities (i.e. segments of the supply chain that are regulated and
and clinics, informal markets, drug wholesalers and traders, where patients should reasonably expect to receive an
and via sale on the Internet [1,12,13]. The impact of these authentic product) across 69 different countries [22]. There
‘fake’ medicines is enormous, as they inflict significant nega- has also been a substantial surge in the number of journal
tive impact on patients’ safety and treatment outcomes, lead publications on the subject, indicating increased attention
to waste, diversion, and fraud and abuse in medicines access from researchers, funding agencies, and the broader health-
and healthcare financing, loss of confidence and commercial care community [23,24].

CONTACT Tim K. Mackey [email protected]

Supplemental data for this article can be accessed here.
© 2017 Informa UK Limited, trading as Taylor & Francis Group
588 T. K. MACKEY AND G. NAYYAR

decades, pharmaceutical development, manufacturing, packa-

Article highlights ging and delivery has become dramatically more extended,
● Our multidisciplinary review uncovered 60 articles from various dis-
globally dispersed and virtual in nature [6,12,28,29]. This pro-
ciplines describing digital technologies, solutions, and innovations in cess of globalization has introduced suites of new players in
the fight against the global trade in fake medicines. different international markets including contract based sup-
● The most mature digital anti-counterfeit technologies included
mobile and RFID-based solutions, both of which use their underlining
pliers, manufacturers, suppliers of raw materials (i.e. active
communication technology platforms to enable more robust fake pharmaceutical ingredient), and trading partners resulting in
drug detection, authentication, and track and trace. a ‘diversification’ of supply networks [28,29]. This means that
● Less mature technologies, such as the use of machine learning, have
yet to be sufficiently commercialized, but show great promise in
medicines constantly change hands and undergo multiple
detecting and preventing the sale and distribution of fake medicines transactions between production and dispensing to the end-
especially via online venues. user patient, with each transaction increasing the risk for
● Blockchain stands out as a potential revolutionizing technology fra-
mework to better ensure a modernized and ‘digitized’ drug supply
falsified and substandard products infiltrating the supply
chain that is more trustworthy, accountable, transparent, and pro- chain [6,12,22].
tected from fake drug infiltrations. Though many global medicines supplier networks are inter-
● While investment in anti-counterfeiting solutions to combat fake
medicines is growing, leveraging the existing policy, legal, and gov-
connected, not all markets share the same risk characteristics
ernance environment to translate these technologies into action is or points of vulnerability [28]. For example, in high-income
critical. countries such as the United States, a smaller number of larger
This box summarizes key points contained in the article. firms manage distribution of the wholesale drug market,
resulting in most patients getting their medicines from large
suppliers that deliver legitimate pharmaceutical products to
licensed retail and hospital pharmacies through a controlled
However, even with increased research, advocacy, surveil- and highly regulated supply chain [30]. However, a smaller
lance and concomitant efforts by regulators and law enforce- percentage of medicines also traverse through the largely
ment to combat fake medicines, the true scope and impact of unregulated ‘gray market’, populated by secondary wholesa-
this global drug safety challenge remains underrepresented as lers, traders, and resellers, where the possibility of sourcing
incidents go undetected, are reported to the wrong agencies, improperly stored, diverted, contaminated, counterfeit or fal-
or kept from the public record by national governments and/ sified medicines substantially increases [30–33]. Such was the
or pharmaceutical companies due to political or commercial case in 2012, when fake versions of the anticancer drug
concerns [16,21,22]. Key risk characteristics of the fake medi- Avastin®, were purchased and likely administered to thou-
cines trade are also inherently difficult to measure given its sands of patients around the USA [34–36].
multijurisdictional nature, politicization of the issue, disagree- Conversely, in low-and lower middle-income countries,
ment on terminology, the complexity and interconnectedness multiple drug supply and delivery systems often run in
of manufacturer–supplier–consumer networks, and the con- parallel within a country resulting in corresponding varia-
stant evolution of the drug supply chain including its rapid tion in efficiency, quality and oversight [12,37,38]. Hence,
globalization [4,6,16,25]. low-income and poor or limited resource settings may be
more susceptible to fake medicines due to underlying chal-
lenges of lack of good governance in national pharmaceu-
tical systems, weak drug quality and regulatory systems, and
1.2. Globalization of the drug supply chain corruption in the health sector [37,39–42]. For example,
Explosive growth in pharmaceutical spending has coincided substandard and falsified versions of antimalarial treatments
with the globalization of the drug supply chain [6,26,27]. The are endemic in many resource poor areas, such as Southeast
structure of the modern pharmaceutical supply chain reflects Asia and sub-Saharan Africa (where studies have estimated
an industry that is now transnational, interconnected, com- that as high as 40–50% of antimalarials may be counterfeit)
plex, and becoming increasing digital. Over the last two directly contributing to hundreds of thousands of

Table 1. Categories and definitions of drug product quality and authenticity.

Terminology Definition
Substandard Substandard medicines are produced by genuine manufacturers but do not meet quality specifications set for them by
National standards and/or National Regulatory Authorities. Substandard medicines are usually the result of poor
manufacturing or manufacturer storage practices; however subpar product quality can be caused by other drivers as
well. For instance, degraded medicines also fall under this category and include genuine drugs that are degraded
and become poor quality by poor storage or handling conditions after leaving the factory
Falsified (previously counterfeit)/falsely Falsified medicines are deliberately and fraudulently produced or mislabeled with respect to identity and/or source.
labeled/spurious Falsified medicines can include both branded and generic medicines. These products can include the incorrect
amount of ingredients, wrong ingredients, no active ingredients, have insufficient quantity of ingredient(s) or be
packaged incorrectly/fraudulently.
Counterfeit Counterfeit medicines are those that do not comply intellectual and industrial property rights, such as registered
trademarks or patent rights
Diverted Diverted medicines are genuine medicines that have been removed or stolen from legitimate markets and sold in
unintended markets or gray markets fraudulently
 EXPERT OPINION ON DRUG SAFETY 589

preventable deaths, exacerbating disease burden, and con- While these solutions can be effective, advances in infor-
tributing to a rise of resistant strains [20,43–46]. mation science, software development, and web-enabled
technologies are transforming security for electronic transac-
tions and supply networks of other industries (such as in the
1.3. Digital ‘gray’ market financial technology and e-commerce sectors). These same
emerging ‘digital’ technologies are also increasingly being
Globalization of consumer markets coupled with the rise of
used to improve performance, management, and interoper-
e-commerce platforms has also resulted in new channels that
ability of the global pharmaceutical supply chain (including
fake medicines can penetrate, including purchase and deliv-
use of IT infrastructures, data analytics, inventory manage-
ery via the Internet [47–51]. Specifically, the accessibility,
ment, and end-to-end supply chains) yet have yet to be fully
anonymity, low-cost, and global reach of Internet-based tech-
leveraged to detect and prevent fake medicines [63].
nologies has enabled the rapid proliferation of online phar-
Despite advances in many digital technologies, the poten-
macies (estimated as more than 35,000 websites), or more
tial application and translation of these solution to address the
simply websites that purport to operate as legitimate phar-
complex drug safety challenge of fake medicines is only
macies via the Internet or mail-order and sell prescription
beginning to take shape. This despite growing importance
drugs direct-to-the-consumer [51–53]. However, the vast
for a digital ‘modernization’ of the drug supply chain, given
majority of these online ‘pharmacies’ conduct business illeg-
that 3.5 billion people are now connected to the Internet and
ally and without appropriate safeguards, including not requir-
95% of the world is connected to a mobile cellular network
ing a valid prescription, operating without a valid license/
[64]. Importantly, these technologies may hold real promise in
certification, and failing to meet national or international
turning the tide in the fight against the fake medicines trade
pharmacy regulations [49–51,54–56] These illicit or ‘rogue’
by tackling supply chain vulnerabilities, but more in-depth
online pharmacies pose a serious threat to global patient
assessment is needed to identify opportunities and barriers
safety as they act as a source and distribution point for
to their realization.
medicines of questionable quality are not subject to the
regulatory safeguards of the controlled supply chain, and
lack clinical oversight from a clinician/physician, pharmacist, 2. Methods
or other trained healthcare professional [51,57].
When consumers purchase medicines from illegal online 2.1. Aim
pharmacies, they become active participants in circumventing The aim of this review was to identify existing and emerging
a regulatory system designed to protect the safety, quality, digital technologies designed to ensure the integrity of the
and appropriate use of prescription drugs, while also creating global drug supply chain by combating fake medicines. We
broader market demand for the global manufacture, distribu- undertake this review to better understand how digital tech-
tion and spread of fake medicines [9,47,51,58]. Consumers also nologies can enable cooperation and coordination among
face cybersecurity risks such as financial fraud, data phishing, different international stakeholders to address a decades-
and infection by computer viruses/malware/spyware that can long public health problem that demands innovative solutions
add to existing health-related harms [51]. Hence, the globali- in order to protect patients globally. We note that we did not
zation of e-commerce has enabled the creation of a ‘digital’ include discussion about traditional forms of anticounterfeit-
pharmaceutical gray market completely separate from the ing technologies that do not specifically have a digital tech-
legitimate supply chain, but in many ways, more convenient nology application (e.g. product serialization, use of packaging
though equally dangerous. Importantly, ongoing challenges authentication, visual inspection solutions, laboratory or for-
regarding ensuring equitable access and affordability to pre- ensic detection technology including but not limited to x-ray
scription drugs remain driving factors in perpetuating this powder diffraction, spectroscopy, nuclear magnetic resonance,
alternative avenue of demand and sourcing [12,16,59,60]. infrared imaging, and liquid chromatography) as these coun-
termeasures have been extensively covered in a 2014 review
article published in PLoS One by Kovacs et al. [45] We also did
1.4. ‘Digital’ supply chain solutions not focus on the review of policies related to public health
As physical and digital vulnerabilities remain exposed, differ- interventions or health system-level interventions (i.e. regula-
ent methods of ensuring the integrity of the global drug tory measures, public education/awareness, and pharmacov-
supply chain are needed to address the unique challenges igilance) as this has been previously examined in systematic
posed by different international markets, supply chain review articles by Hamilton et al. in Health Policy and Planning
dynamics, and legal jurisdictions. Primarily, fake medicines and Fadlallah et al. in Pharmaceutical Medicine respectively,
countermeasures have relied upon serialization (i.e. identify- both recently published in 2016 [17,58].
ing a medicine by using unique printed codes, images, or
holograms on packaging to verify authenticity), authentica-
2.2. Literature review
tion (i.e. scanning a medicine product at point of supply
through to the patient to verify authenticity), and track and We first conducted a literature review for journal articles, origi-
trace technology (i.e. logistic technology that follows the nal research, conference papers, case reports, technology
current and past locations of medical products through the reviews, commentaries and news reports that were indexed in
supply chain) [18,45,61,62]. four scholarly databases. This included conducting search term
590 T. K. MACKEY AND G. NAYYAR

queries on the databases PubMed (Medline), IEEE Xplore, ACM subject has increased at the highest rate over the past 5 years
Digital Library, and Google Scholar. The rationale for choosing [24]. A visual description of how we conducted the literature
these databases was the interdisciplinary nature of the study review and the keywords used are provided in Figure 1 and
aims, which required a review of the science/health literature detailed below.
(PubMed-indexed journals that cover life sciences and biome- After our initial search results, we applied an inclusion and
dical topics), studies on information, communication and engi- exclusion criteria that filtered results by reviewing abstracts of
neering technologies (IEEE Xplore-indexed articles that focus on extracted articles. We first excluded articles that did not discuss
scientific and technical content published by the Institute of application of technology to fake medicines (e.g. discussed
Electrical and Electronics Engineers [IEEE]), research on other fields of study or other counterfeit goods such as con-
advances in computing sciences (ACM Digital Library indexes sumer products, currency, electronic components/equipment,
various journals, conference proceedings, technical magazines, cosmetic products, foods, cigarettes, or dietary supplements)
newsletters and books in the computing literature), and a gen- and then excluded articles that included fake medicines but did
eral search of the literature (Google Scholar indexes a variety of not discuss forms of digital technologies and solutions (e.g.
peer review papers, theses, preprints, abstracts, and technical laboratory-based technologies not connected to the Internet,
reports for a variety of disciplines). survey instruments or analysis of secondary data, discussion of
We limited our searches to English-language articles pub- professional guidelines and/or recommendations, policy and
lished between 2010 and 2016. Our search queries included the regulatory related topics, and traditional forms of packaging
combination of two keyword categories: (a) terms associated authentication and serialization).
with fake medicines and online pharmacies; and (b) terms In order to expand our search and capture emerging and new
associated with emerging ‘digital technology’. We define ‘digi- technologies that may have been absent or not extensively
tal technologies and solutions’ as those that are: (1) enabled by covered in the academic literature, we also reviewed gray litera-
Internet-based technologies and/or platforms (e.g. online por- ture sources using structured natural language web searches
tals and management systems, Internet-based supply chain with a similar combination of keywords on the popular Google
tools, cloud-connected databases, social media-based applica- search engine. We retrieved and reviewed information sources
tions); (2) use mobile or wireless technologies (e.g. mobile including technical reports, reports from government agencies,
phone applications or wireless transmitting devices that con- news reports from media outlets (i.e. nonscientific sources),
nect to the Internet); (3) use of algorithms or other advanced company websites, blogs, and press releases, information from
computational methods for data analysis; and (4) solutions that nongovernmental organizations/trade associations/solution pro-
share common IT-platforms, web connected databases or uti- viders/supply chain companies, and information from govern-
lize cloud-based systems. ment and regulatory agency websites. We specifically focused on
Keywords were queried in the Title/Abstract field using existing and emerging technology already identified and/or
advanced search function settings for PubMed, IEEE Xplore, referenced in our academic literature review (e.g. specific types
and ACM Digital Library databases. For Google Scholar, we of technologies, names of companies, names of solutions) and
used natural language queries limited in time frame of pub- reviewed results carefully to identify case studies, updates, and
lished date and excluded results of published patents. We other supplemental information. Gray literature searches were
chose a 6-year literature review period as this study is focused conducted from November 2016 – January 2016 and were lim-
on relatively new, emerging, or innovative technologies and ited to the first five pages of results for each keyword search
based on findings indicating that published literature on the query combination.

Figure 1. Literature review search methodology and characteristics.

 EXPERT OPINION ON DRUG SAFETY 591

3. Results consumers against fake medicines appeared to be among

the most mature, and are particularly promising given their
Our review of the literature identified five distinct categories
potential for scalability and user adoption. Primarily, these
of ‘digital’ technology solutions and platforms that are either
solutions seek to leverage the growing capabilities of mobile
existing or emerging in the fight against fake medicines (see
phone device platforms, software, built in sensors, cameras,
Figure 2 for summary). Overall, the most mature of these
and ability to connect to GPS, wireless networks and the
digital technologies were the categories of mobile solutions
Internet, by using mobile technology as a complementary
for fake medicines authentication and tracking, the use of
solution to existing anticounterfeiting technologies.
Radio-Frequency Identification (RFID) coupled with other digi-
Our review of mobile technologies identified six key com-
tal tools to better secure the drug supply chain, and the
mercial solutions that approach the problem in different ways
development of web-based platforms to better verify legiti-
but all share a mobile platform as a unifying technology back-
mate versus illegal online pharmacies. It is notable that solu-
bone (see Table 2). These mobile technologies span from
tions within this first category of technology all have
authentication services, track and trace solutions, and pill
commercially viable applications. Outside of these more estab-
image recognition tools. Many of these technologies have
lished technology formats, other solutions such as the applica-
launched within the past decade coinciding with increased
tion of machine learning, advanced text processing, and
uptake and advances in mobile features; with technologies
blockchain technology, are still in their emerging phases,
such as mPedigree’s launching as early as 2005 to the more
where experiments, conceptual designs/frameworks, use
recent market entry of Authenticateit in 2016 [65].
cases, and early-stage technology was predominant, though
Among the six companies identified in this space, five used a
research and investment appears to be growing. Collectively,
form of mobile authentication and/or mobile-based track and
emerging digital technologies are at varying stages of matur-
trace solution (see Sproxil Case Study #1 in Supplemental
ity and mainly target pharmaceutical companies, governments
data). Furthermore, most companies had pivoted from original
(e.g. drug regulators, customs officials, law enforcement), and
models of product serialization (e.g. scratch-SMS solutions) to
pharmaceutical manufacturers and retailers, though end-user
supplementary security-as-service solutions that track medicine
patients are growing as a potential user base. Below we detail
products across the supply chain [33,65,66]. An exception to
each technology category and provide select case studies
this, and a leader in this context was the mPedigree platform,
illustrating their practical application.
which from its early launch, used product serialization in com-
bination with an electronic pedigree (e-pedigree) for increased
security enabling verification of both product and transaction
3.1 Mobile technologies
integrity [66–68].
Few technologies are as globally ubiquitous as the mobile In addition to the case studies of commercialized technol-
phone, which now commands approximately 3.6 billion global ogies reviewed, several research papers described experimen-
mobile-cellular subscriptions [64]. Given the widespread pre- tal or proof-of-concept studies aimed at leveraging mobile
sence of mobile phones in both developed and developing platforms to develop higher-throughput, lower cost, and
economies, wireless or mobile driven solutions to protect more user-friendlier authentication and track and trace

Figure 2. Visual summary of existing and emerging categories of digital technologies to combat fake medicines.
 592

Table 2. Categories and definitions of drug product quality and authenticity.

Services
Supply
Mobile Point of sale Supply chain chain
Products Description provided in the literature Reach authentication authentication coordination Key stakeholders
Sproxil Sproxil is a mobile product authentication solution. Enables verification by using a mobile phone, 20 million x x Pharmaceutical,
[Founded 2009] QR code on the product and a free text message. If a fake product is found, consumers are also verifications1 governments, distributors,
given a hotline number to call in order to report the fake product, so the issue can be directed retail outlets and patients
to the appropriate authorities
T. K. MACKEY AND G. NAYYAR

mPedigree mPedigree is a mobile pedigree identification record and product authentication solution powered 10 million packs x x Pharmaceutical,
[Founded 2007] by a cloud-based system offered by Hewlett Packard. mPedigree refers to mobile short code of medicine2 governments, distributors,
platform (using QR codes and barcodes) to interconnect GSM mobile networks via a central retail outlets and patients
registry wherein pedigree information of product brands belonging to participant manufacturers
are stored. mPedigree also offers other supply chain security and coordination solutions for retail
pharmacies

PharmaSecure PharmaSecure is a mobile product authentication solution focused on end-user verification. 40 countries, 60 x x Pharmaceutical, retail
[Founded 2007] Medicine packets are linked with a unique code (customized to market and regulation including pharma outlets, and patients
alphanumeric barcodes etc.). Customers who purchase the drug can then text message that companies3
code to the PharmaSecure number and receive a response (voice, web or text) that 500 m units
authenticates the medication and provides expiration dates and related information. More of medicine
recently, distribution wide services have also been provided secured4

Epothecary Epothecary is a mobile product track and trace supply-chain security solution proposal that uses NA x x x Pharmaceutical, distributors,
[Published 2009] camera phones to scan unique ‘glyphs’ attached to each medicine unit, at each level of retail outlets and patients
No image available packaging, distribution storage, and sale via SMS verification. This solution can also track
quantity sold and GPS coordinates of the products across the supply chain
MedSnap MedSnap is a mobile medicine image recognition that takes images via phone of actual pills and NA, x Governments and patients
[Founded 2011] runs it across their authentic pill image library to provide a wide range of information and commercially
verification of the product available

(Continued )
 EXPERT OPINION ON DRUG SAFETY 593

solutions. This includes solutions that use mobile phone appli-

governments, distributors,
cations to authenticate and track individual medicine capsules

Key stakeholders
using upconversion 3D fluorescent QR codes, Android mobile
applications that enable consumers to check the regulatory

Pharmaceutical,

and patients
status of medicines with the Ministry of Health, and a pro-

Chabra E. Source Code: PharmaSecure Goes Mobile in Battle Against Fake Drugs. 2013; available at: https://www.theguardian.com/global-development/2013/may/09/source-code-pharmasecure-fake-drugs
posed mobile technology medicine verification framework
using a data matrix to mitigate security vulnerabilities of
existing commercial solutions [66,69,70].
Importantly, mobile phones can act as the primary device for
authentication authentication coordination

integration with other physical platforms enabling image cap-

Supply
chain

ture and data processing through cameras and software while

x

simultaneously connecting these platforms to the Internet or

cloud-based services to conduct real-time authentication and
Point of sale Supply chain

analysis of drug specimens [71,72]. This includes the concept of

Services

Mobile Product Authentication (MPA), where short message

x

services (SMS), image capture, and code scanning can allow

authentication of medicines by validating information hosted
on cloud technology or other secured connected databases
[65]. An example of this type of innovation included a proof-
x

of-concept 3D-printed cradle that holds a mobile phone run-

ning a special mobile software application that uses portable
thin-layer chromatography analysis to identify falsified or sub-
standard medicines via image capture [71,72].
Reach

Sproxil Surpasses 20 million Verifications, 2015, available at: https://www.sproxil.com/blog/sproxil-surpasses-twenty-million-verifications

NA

Advantages of using mobile-based authentication and

track and trace solutions include that they require less infra-
structure, are more cost-efficient to scale, can be more user
friendly, can provide real-time analysis when connected to
Authenticateit is a mobile product track and trace consumer and supply-chain security solution.

cloud databases, are already wireless and/or GPS-enabled,

The Authenticateit smartphone app will enable clinicians and patients will scan products

and have the potential to engage patients as participants in

mPEDIGREE, 2013, available at: http://www.africanstrategies4health.org/uploads/1/3/5/3/13538666/mpedigree.pdf

a collective security solution [67,73]. Furthermore, mobile track

and trace technologies can provide benefits beyond securing
the drug supply chain including reduction in medication
errors, automated pharmacy billing and refills, and support
for product recalls [18]. Recognizing these benefits, the
Description provided in the literature

Nigerian Ministry of Health mandated pharmaceutical compa-

nies (selling antibiotics and antimalarials) to implement a form
PharmaSecure, About Us, 2016, available at: http://www.pharmasecure.com/about-us/

of mobile authentication in 2013; similar legislation has also

been introduced in India [18,74,75].
However, even with its considerable benefits, scaling
mobile solutions to effectively combat fake medicines relies
heavily on: (1) regulatory mandates for manufacturers to par-
ticipate; (2) adoption of technology by different users/data
points in the supply chain; (3) awareness and willingness of
pharmacists to engage and educate supporting these solu-
tions; and (4) raising overall consumer awareness about fake
medicines to increase user participation. Additionally, while
the proliferation of mobile authentication solutions has the
short-term benefit of empowering more actors across the
supply chain, there are also risks of having multiple privately
owned authentication solutions serving the same market and
lacking sufficient interoperability [76]. More specifically this
could cause fragmented documentation, unreported cases of
fake medicines from pharmaceutical manufacturers, and multi-
ple and disparate sources of data, similar to current challenges
Table 2. (Continued).

Medicines 2016]

faced by the fragmented network of public health surveillance

[Expanded for
Authenticateit

for fake medicines [1,16,22]. Finally, mobile verification in iso-

lation does not prevent fraud and should not to be used in
Products

Sources:
Mobile

place of traditional pharmacovigilance or traditional post-mar-

ket surveillance systems [12].
1
2
3
4
594 T. K. MACKEY AND G. NAYYAR

3.2. RFID-based solutions (versus packaging) to enhance security measures (see

TruTag™ Case Study #2 in Supplemental data) [79,88,90].
Radio Frequency Identification (RFID) is a rapidly emerging tech-
Another example was an experimental system that used
nology in various industries and is becoming a mainstay in
‘chemometric authentication’ using nuclear quadrupole reso-
supply chain management, but has only recently become more
nance spectroscopy (a quantitative radio frequency spectro-
widely embraced by stakeholders in the pharmaceutical supply
scopic technique) to both authenticate and verify the actual
chain [28,77,78]. At its core, RFID is a technology that uses
contents of medicines at various stages in the drug supply
electromagnetic fields to automatically track and identify items
chain [90]. The second highly engaged category included
affixed with tags containing electronically stored information.
RFID authentication solutions. These focused on mitigating
Hence, RFID and related standards (such as electronic product
vulnerabilities from security attacks against data transmission
codes [EPCs]), enable the tracking and management of inventory
(including desynchronization attack, impersonation attack,
throughout the manufacturing and distribution process, while
reapplication attack, parallel session attack, modification
also allowing remote authentication that enables identification
attack, denial-of-service attack, and tag cloning), securing
of falsified, substandard, and adulterated medicines, while also
anonymity and untraceability, using batch authentication to
acting as a critical tool during product recalls [25,28,62,79,80].
improve process efficiency, and better securing mutual
Prior to RFID, the industry primarily relied on barcodes
authentication [82,85,91,92].
affixed to medicines packaging for authentication and track-
Importantly, the majority of RFID solutions examined were
ing, a technology particularly susceptible to counterfeiting
aimed at improving and acting as complementary solutions to
and limited in data storage capacity [28,33,46,81]. In contrast,
existing anticounterfeiting product authentication and track
RFID operates under a system where a tag (transponder) with
and trace strategies (e.g. imaging technologies, 2D-barcodes/
unique identification information of tagged-objects (i.e. affixed
QR codes, cryptography, mobile platforms, chemical finger-
to drug packaging) transmits information through radio waves
prints, etc.) by using RFID to securely transmit data and validate
or wireless channels to a reader (interrogator) that extracts
it over the Internet or in the cloud [79,88]. Hence, RFID shows
data on the product/lot that are then captured and stored in
promise as an underlying technology to better ‘digitize’ the
computer/server systems or web portals [28,62,77,82]. Though
global drug supply chain for the dual purposes of improving
several commercial pharmaceutical RFID solution providers
logistic performance and enhancing drug safety.
exist, barriers to universal adoption include challenges asso-
ciated with interoperability and integration across foreign
firms, the need for standards setting, costs and time required
3.3. Advanced computational solutions
for implementation, and questions about the utility of RFID IT
investment [28,33,58,79,83]. These barriers exist despite legis- A separate category of anticounterfeiting solutions (reported
lative requirements in some countries that require forms of ‘e- primarily in the computer science literature) focused on the
pedigree’ (i.e. an electronic document that provides data on use of advanced computational methods for the detection
the history of a batch or lot of drugs enabling traceability and and mitigation of cybercriminal activities, specifically including
transparency) that may rely on RFID technology illicit online pharmacies and drug supply-chain incursions.
[28,46,58,77,79,84]. Solutions were primarily grouped into two categories, most
Novel approaches attempting to address some of the under- in conceptual, experimental, or proof-of-concept phase,
lying commercial and technical challenges of RFID adoption are including: (1) use of machine learning algorithms to better
described in several studies, most of which were extracted from detect and classify illicit online pharmacies through text
the IEEE database. These studies explore ways to improve the mining and content analysis; and (2) use of machine learning
security, usability, and efficiency of RFID-enabled supply chains to detect irregularities or patterns of counterfeit penetration in
including: (1) protecting RFID from security and privacy breaches; the drug supply chain.
(2) proposing systems to better integrate RFID information from The development of machine learning algorithms applied
pharmaceutical supply chain participants (including integration to ‘big data’ is a growing field in many disciplines including
of RFID and EPC data); (3) development of algorithms using health, medicine, and drug safety, and has formed the basis
secure multiparty computing and differential privacy to secure for a new research area known as and ‘digital’ surveillance or
e-pedigree; (4) creating micro RFID tags for individual pills or ‘infoveillance’ [93–98]. Specifically, machine learning is a sub-
capsules (instead of affixing tags to packaging); (5) proposals to field of computer science and a type of artificial intelligence
include temperature and humidity conditions in e-pedigree for that allows computers to learn without being explicitly pro-
cold chain management; (6) the use of centralized databases/ grammed when exposed to new data. The machine learning
systems for supply chain information transmission; and (7) devel- utilized to address illicit online pharmacies focuses on training
oping more robust RFID authentication protocols and processes algorithms that can shift through large volumes of machine-
(including use of cryptography and Near Field Communications readable content and automatically classify the content char-
(‘NFC’) via mobile phones) [78,80–82,84–89]. acteristics such as websites, email spam, and social media
Two distinct categories appeared to have the highest communications. This method is useful in detecting criminal
levels of research activity. The first category focused on activities that may follow certain distinct patterns or present
creating lower cost, smaller, more resilient, safer, and edible as anomalies in a large set of data. Machine learning has also
forms of RFID tags that can be applied to individual tablets been used to address other diverse drug safety topics
 EXPERT OPINION ON DRUG SAFETY 595

including data on post market surveillance, adverse events, due to challenges faced by the need for human interpreta-
drug toxicity, and drug discovery [93,99–106]. tion of results, Banerjee et al. developed an image recogni-
The first category of studies used different applications of tion classifier designed to automatically compare PAD visual
machine learning to detect illicit online pharmacy content testing results to stored images of authentic drug PAD sam-
and communications by identifying and classifying: (a) tweets ples, with some models reporting high accuracy of classifica-
(on the popular microblogging platform Twitter) promoting tion models [115]. They also describe plans to develop
illicit online pharmacy sales of prescription controlled sub- mobile message services so users can send their PAD images
stances; (b) a framework for text mining Facebook and in order to build a larger test dataset to improve their classi-
Twitter content to detect negative sentiment about drug fier models [115].
products that may signal counterfeiting; (c) Internet and Though promising, advanced computational methods
website network information and content level features (e.g. that leverage machine learning to fight online and physical
HTML text, images, network stack information, other meta- distribution of fake medicines appear to lack sufficient
data) indicating counterfeiting activities; and (d) cluster ana- investment as we were unable to identify a commercially
lysis that identifies large website networks involved in available solution fully utilizing this technology approach.
pharmaceutical cybercrime and spam [96,97,103,107,108]. This despite machine learning underpinning several leading
Another study used human annotation (i.e. not machine consumer platforms (e.g. video and music streaming ser-
learning) to analyze ‘signal’ data on website trust features vices, web search engines, online advertising) and actively
(e.g. verification seals, store presence, product selection, ful- being used by several industries including the healthcare
fillment features, and health content) to accurately classify sector for other issues.
regulated versus unregulated online pharmacies, a method
that potentially could be scaled if adapted for use with
machine learning protocols [109].
3.4. Online pharmacy verification solutions
Three particularly innovative studies combined web crawling
(i.e. using crawlers/bots to mine content from webpages) and Our review also captured four categories of web-based solu-
machine learning to detect and classify different actors in the tions designed to verify and educate consumers about the
online pharmacy ecosystem. The first describes a novel compu- dangers of illicit online pharmacies. These technologies serve
tational system named ‘PharmGuard’ that uses a web crawler the purpose of providing consumers with reliable information
and supervised machine learning algorithms to automatically about the legal status of an online pharmacy and whether it
identify search engine indexed online pharmacy websites and has been appropriately vetted by regulators in their country of
related advertisements [110]. Another study described the operation. Technologies in this category include: (1) website
development of an adaptive learning algorithm called recursive seals; (2) commercially available website verification services;
trust labeling (RTL) that was tested to detect fake medical and (3) a new top-level domain name for legitimate online
websites (including online pharmacies) and reported over a pharmacies. Different from other technologies reviewed, web-
90% detection accuracy when deployed over nearly one million based solutions focus on protecting consumers at the point-
websites [58,111]. A final study described a methodology that of-sale, while also rely on consumer awareness, education and
automatically extracts web page features for profiling online user participation in order to be effective.
storefronts to train a classifier to accurately identify affiliate The first category comprised of website seals, which are
marketing programs that promote and spam information essentially images, links or objects displayed on pharmacy web-
about online pharmacies [112]. sites of accredited or legitimate online retailers. They are usually
A second category of machine learning technologies acquired through national, regional, or global agencies that
involved developing algorithms to detect fake medicines by provide a form of accreditation or certification of legitimacy
mining data from the broader drug supply chain. This included and quality. The National Association Boards of Pharmacy
an article describing a pattern-mining algorithm used in com- (NABP) in the United States implemented the Verified Internet
puter simulations to detect counterfeit medicines from track Pharmacy Practice Sites Seal or ‘VIPPS’ seal as early as 1999 in
and trace records (such as RFID event data) [113]. Another response to the rise in illicit online pharmacies [116]. The seal was
study described the use of economic cybernetics to monitor provided to pharmacies via a rigorous application process,
differences in pharmaceutical supply flow to detect irregula- inspections/audits, and a recurring fee to participate in the pro-
rities that could constitute fake medicine events [114]. gram. Similarly, in 2015, the United Kingdom launched the EU
In a completely different application of machine learning, common logo for all online pharmacies and retailers offering
deep learning models (a branch of machine learning based medical products for ‘human use in the European Union’ [117].
on artificial neural networks that has commonly been used in The UK common seal, like VIPPS is not intended to be used in
speech and image recognition) were used in combination isolation to verify website authenticity, but instead is activated
with physical counterfeit drug detection devices, specifically when the logo is clicked and the user is redirected to a separate
Paper Analytical Devices (PADs) [115]. PADs are paper-based verification page. However, for website seals to be successful
testing kits embedded with reagents that react with chemical there must be existing consumer knowledge on the dangers of
compounds producing a set of distinctive color patterns that illicit online pharmacies, consumers need to be aware the seals
can be visually compared to stored images of authentic exist and their purpose, and duplication or counterfeiting of
products indicating whether a drug is fake [115]. However, online seals needs to be prevented.
596 T. K. MACKEY AND G. NAYYAR

A second category includes website verification services economic and supply transactions), execute of ‘smart con-
that comprise of large databases containing information tracts’, and operate an immutable, shared, and encrypted
about online pharmacies (usually collected through web transaction ledger that can be used to track and trace goods
crawlers) that enable consumers to check the status of an across the supply chain [124–127].
online pharmacy’s by querying its URL. LegitScript LLC is a In the context of fake drugs, the application of blockchain
commercial leader in this space and partners with several has the potential to: (1) track and trace pharmaceutical raw
private companies, including Google, Amazon, Visa, and materials and finished product from manufacture to end user
Bing (Microsoft), to monitor and identify fraudulent online in an immutable and shared e-pedigree-based digital ledger;
pharmacies. It also operates a website that allows free pub- (2) provide greater transparency and enable detection of fake
lic searches so that consumers can check an online phar- drugs in the supply chain by allowing blockchain participants
macy’s legitimacy via a searchable database [51,118,119]. to verify the authenticity of data; (3) integrate anticounterfeit
However, not all website verification services may be repu- devices into the ‘Internet of Things’ and better enable detec-
table and they also require constant monitoring and updat- tion and authentication; and (4) could serve as an open
ing as new websites are removed and created and as standards technology to enhance information sharing across
existing ones change or potentially become noncompliant unrelated databases and different actors in the drug supply
[50,51,57]. chain [127–129]. This could potentially transform a block-
An alternative approach to website verification services is chain-enabled drug supply chain into a more trustworthy,
one that is taking advantage of recent changes in Internet accountable, and transparent shared and open data architec-
governance. In 2011, the Internet Corporation for Assigned ture that could cross multiple supply chain actors and
Names and Numbers (ICANN) launched a new program to jurisdictions.
create thousands of new generic top-level domain (gTLD) Despite its potential to better establish drug supply chain
names (i.e. the highest level of the Internet name space or provenance, we were only able to extract a single 2016 IEEE
simply everything after the final dot in a web address) includ- non-research article that summarized a few blockchain pro-
ing domains associated with health services (e.g. .health, . jects initiated by different organizations and explored it as a
doctor, .medical) [120–122]. Included in the new gTLD propo- potential solution for fake medicines among other healthcare
sals was an application for a .pharmacy domain with NABP as problems [125]. Though there was little literature on the sub-
the registry operator. The .pharmacy domain’s purpose is to ject, our review of the gray literature turned up several exam-
act as a dedicated name space on the Internet to host legit- ples of prototypes, use cases, and research and educational
imate online pharmacy websites and other related resources initiatives for pharmaceutical supply chain-related blockchain
vetted through NABP’s approval processes (see .pharmacy activities. This included startup companies, such as Chronicled,
Case Study #3 in Supplemental data for more details). Inc., which has launched prototype technology combining
Applications to apply for a .pharmacy domain are now avail- NFC embedded adhesive seals that are registered and verified
able and if successfully adopted would act as a ‘built-in’ on a blockchain, a project by iSolve, LLC that simulates how
verification tool for online pharmacies by signaling to consu- blockchain can be used to track medicines in a theoretical
mers that any website with a .pharmacy web address is legit- supply chain, a use case by BlockVerify for an anticounterfeit-
imate [123]. However, many consumers are not aware of the ing platform using verification tags verified via blockchain
new gTLDs, and it remains to be seen if legitimate online technology, and the presentation of conceptual design and
pharmacies will use this platform to market the credibility use cases by Rubrix by Deloitte (spun off from major profes-
and safety of their services. sional service firm Deloitte Touche Tohmatsu Limited)
[125,127–132].
Other examples of blockchain pharmaceutical supply chain
3.5. Blockchain technology
initiatives included the multistakeholder BlockRx project to pilot
A final emerging technology category we identified was lever- blockchain technology in the pharmaceutical sector, the open
aging blockchain technology to combat fake drugs and dyna- source collaboration Hyperledger (backed by the Linux
mically enhance the security of the drug supply chain. Foundation) to explore use of blockchain to improve pharmaceu-
Fundamentally blockchain is a secure distributed digital ledger tical supply chain security, hackathon contests and boot camps
(i.e. simultaneously shared across multiple users/locations and that have featured conceptual solutions aimed at ensuring quality
not stored in a single location) made up of ‘blocks’ of contin- and accountability in the supply chain, and educational and out-
uous transaction information. Blockchain technology has been reach initiatives by IEEE Standards Association (including a virtual
the subject of widespread attention, investment, and industry blockchain workshop and webinars) [125,132–135].
hype, given its potential to share, sync, and better secure Though still in its relative infancy, the march toward com-
(through cryptography and ‘miners’ that validate and chain mercialization of blockchain technology to address the fake
together blocks of transaction data without the need for a medicines trade appears to be outpacing research efforts. This
central authority) transaction information and data via a peer- indicates that rapidly emerging technologies backed with
to-peer, distributed and decentralized database structure strong private sector investments may bypass early stage
[124–126]. Best popularized as the underlying technology for research and experimentation typically reported in academic
the cryptocurrency bitcoin, blockchain solutions can be used journals, though the success of blockchain to combat fake
to record and authenticate transfers of information (including drugs remains to be realized.
 EXPERT OPINION ON DRUG SAFETY 597

4. Conclusion authentication and transmission of data that can be moder-

ated by various forms of technology (including mobile and
Securing pharmaceutical supply and delivery networks in the
cloud-based applications), but also has the potential to act as
age of globalization represents a significant challenge for gov-
a vehicle for more robust information sharing across different
ernments, regulators, and pharmaceutical companies. However,
data points in the supply chain. Blockchain, albeit less mature,
without effective solutions, patients often bear the ultimate
represents a potentially revolutionizing technology as it seeks
burden of poor quality and fake medicines at the cost of their
to fundamentally change how stakeholders share drug supply
health, finances, and sometimes with their lives [12]. As crim-
chain information via a more trustworthy, secured, and acces-
inals become more sophisticated and supply networks more
sible distributed and decentralized digital ledger.
complex and diverse, new technologies to prevent, detect and
Another key observation was that many of these new
respond to fake medicines need to undergo a continuous
technologies were specifically designed to overcome existing
process of improvement, implementation and evolution in
barriers of adoption and implementation faced by traditional
order to ensure drug safety in the twenty-first century [79].
anticounterfeit technology. Many forms of anticounterfeit
Though our study focused on existing and emerging ‘digital
technologies have failed to scale due to inherent limitations
technologies’, the majority of articles published on fake medi-
such as the high costs of lab-based methods, lack of standards
cine solutions concentrated on traditional forms of laboratory
on testing for products, and a dearth of durable versions of
and field-based technologies for detection and testing, medi-
these technologies needed for field deployment [23,24,45]. In
cines packaging authentication, and enhanced pharmacovigi-
response, many of the digital anticounterfeiting technologies
lance used to test products [7,18,58,61,69,79,136–139]. Though
reviewed were designed to specifically address these limita-
some of these ‘traditional’ solutions included cutting-edge
tions by using lower-cost components, lowering equipment
innovation, including hand-held and/or portable laboratories
and infrastructure costs (such as using existing mobile phones
(e.g. Portable Raman spectrometer, GPHF Minilab®, and US
and cellular networks in lieu of a complete device architec-
FDA CD3+ counterfeit device), molecular fingerprinting (includ-
ture), and using machine learning to automatically analyze
ing use of physical chemical identifiers and nanotechnology/
large amounts of data with minimal human interaction.
nanoparticles), and fabrication of advanced anticounterfeit
Technologies, such as web verification services and mobile
packaging using nano- or micro-materials, they did not meet
solutions, were also designed to overcome adoption barriers
our criteria of leveraging digital technologies that could enable
experienced by end-users by educating and engaging the
them to be wirelessly/Internet enabled, networked, and better
public in the fight against fake medicines. Despite potential
integrated into other anticounterfeiting solutions
advantages, commercialization of many of these solutions is
[45,61,79,140,141]. However, it is clear that these solutions
still in its infancy, with ongoing questions regarding utility,
remain critical tools in the fight against fake medicines, as
cost-effectiveness, and the lack of incentives (such as legal or
they are complementary to digital solutions reviewed here.
regulatory mandates) likely hindering greater investment.
In contrast, our review of existing and emerging ‘digital’
Finally, though digital technologies have the potential to
technologies points to an overall evolution in anticounterfeit
lower costs, enhance supply chain performance, optimize
solutions design and conceptualization and leads us to some
information capture and data transmission, and offer users
key conclusions. First, many of the digital technologies we
greater convenience, they also carry the potential for
reviewed share a common characteristic: they do not operate
increased security vulnerabilities and create opportunities for
in isolation. In fact, the underlining digital technologies they
privacy and data breaches. Hence, another category of solu-
utilize (e.g. wireless, Internet, and radio-enabled capabilities)
tions identified focused on addressing cybersecurity concerns
make them both ubiquitous and also acts to liberalize their
(such as data authentication and data cloning) inherent to
platforms away from technology designed in isolation, as they
these technologies that can be exploited by criminals and
share the ability to connect and interact with a whole array of
hackers. In this sense, certain types of technology merely
information sources, devices, users, and stakeholders across
serve to counteract new risks that emerging technology intro-
the global drug supply chain. For example, digital solutions for
duce, a critical factor when dealing with the profitable and
pharmaceutical product authentication we reviewed have the
criminal nature of this activity.
potential to complement and enhance traditional security and
anticounterfeiting measures (such as packaging authentica-
tion including overt and covert physical holograms or seals)
5. Expert opinion
by offering scalability, being more user friendly, acting in real-
time, and being more cost-effective to deploy [62,73]. The global market for anticounterfeiting solutions is pro-
Further illustrating this point, mobile and RFID anticounter- jected to mature into a $35 billion dollar industry [18].
feit solutions, the two technologies that were the most Reflecting this increased attention and investment, over
mature, serve as a digital backbone for other types of innova- the past 7 years, the landscape for fake medicines technol-
tions. Mobile-based solutions primarily focused on leveraging ogies has significantly increased, with more than 40 unique
the growing features and software capabilities of mobile technologies being commercialized and over half of them
phones to better enhance medicine authentication and now available for use [45]. While this is encouraging, gov-
expand track and trace along the spectrum from paper, elec- ernments, regulators and pharmaceutical companies con-
tronic and now mobile pedigree solutions. Relatedly, at its tinue to struggle with how to utilize forms of traditional
core, RFID is simply a technology framework for automatic and digital anticounterfeiting technologies that are being
598 T. K. MACKEY AND G. NAYYAR

developed, while also determining how they best fit with 4. Attaran A, Barry D, Basheer S, et al. How to achieve international
their individual pharmaceutical product offerings, diverse action on falsified and substandard medicines. Bmj. 2012;345:
e7381.
markets, geography, and unique supply chain vulnerabilities.
5. Mackey TK. Global health diplomacy and the governance of coun-
Fortunately, the international legal, policy, and regulatory terfeit medicines: a mapping exercise of institutional approaches
environment needed to mobilize stakeholder rhetoric into [Internet]. ghd-net.org. 2013 [cited 2013 Jul 1]. Available from:
action may be taking shape. This includes renewed efforts in http://www.ghd-net.org/sites/default/files/Global%20Health%
global governance to fight fake medicines including regional 20Diplomacy%20and%20the%20Governance%20of%20Counterfeit
%20Medicines.pdf
treaty instruments such as the Council of Europe’s
6. Woo J, Wolfgang S, Batista H. The effect of globalization of drug
MEDICRIME Convention that entered into force in 2016, the manufacturing, production, and sourcing and challenges for amer-
Council of European Union’s Falsified Medicines Directive, ican drug safety. Clin Pharmacol Ther. 2008 Mar 1;83(3):494–497.
domestic laws such as the United States’ 2013 Drug Supply 7. El-Jardali F, Akl EA, Fadlallah R, et al. Interventions to combat or
Chain Security Act, and other national and local laws and prevent drug counterfeiting: a systematic review. BMJ Open. British
Med J Publishing Group. 2015;5(3):e006290–0.
decrees [5,16,58,84,142,143]. This emerging global drug-
8. New W WHO board agrees to drop the word “Counterfeit” after 30
safety policy environment could act as a catalyst for the years [Internet]. ip-watch.org. 2017 [cited 2017 Jan 30]. Available
translation of the digital technologies we have identified from: http://www.ip-watch.org/2017/01/30/board-agrees-drop-
into real-world solutions, tools we argue are critical in word-counterfeit-30-years/
addressing a drug supply chain that continues to become 9. Clark F Rise in online pharmacies sees counterfeit drugs go global.
The Lancet. Elsevier. 2015 Mar 10;386(10001):1327–1328.
more globalized, digital, and a lucrative target for criminals
10. WHO. Substandard, spurious, falsely labelled, falsified and counter-
engaged in the international trade in fake medicines. feit (SSFFC) medical products [Internet]. WHO World Health
Organization. 2016. [[cited 2017 Jan 1]]. Available from: http://
www.who.int/mediacentre/factsheets/fs275/en/
Acknowledgments 11. Blackstone EA, Fuhr JP, Pociask S The health and economic effects
of counterfeit drugs. Am Health Drug Benefits. Engage Healthcare
First author would like to thank the IEEE Standards Association for their Communications, LLC. 2014 Jun;7(4):216–224.
invitation and his participation as a problem mentor in the IEEE Virtual 12. IOM. Countering the problem of falsified and substandard drugs -
Blockchain Workshop, Advancing HealthTech for Humanity Series. ™ institute of medicine [Internet]. iom.edu. 2013 [cited 2013 Feb 25].
Available from: http://www.iom.edu/Reports/2013/Countering-the-
Problem-of-Falsified-and-Substandard-Drugs.aspx
•• This is a comprehensive report.
Funding 13. Kohler JC, Pavignani E, Michael M, et al. An examination of phar-
This paper was not funded. maceutical systems in severely disrupted countries. BMC Int Health
Hum Rights. 2012 Dec 6;12(1):34.
14. Delepierre A, Gayot A, Carpentier A. Update on counterfeit antibiotics
worldwide; public health risks. Med Mal Infect. 2012 Jun;42(6):247–255.
Declaration of interest 15. Venhuis BJ, Keizers PHJ, Klausmann R, et al. Operation resistance: A
T Mackey is a non-compensated member of the Alliance for Safe Online snapshot of falsified antibiotics and biopharmaceutical injectables
Pharmacies (ASOP), a 501(c)(4) social welfare organization engaged on the in Europe. Cohen PA, Venhuis BJ, Brandt SD, editors. Drug Test
issue of illicit online pharmacies, academic advisory board. T Mackey Anal. 2016 Mar;8(3–4):398–401.
received funding from ASOP for a pilot research grant exploring the 16. Mackey TK, Liang BA. Improving global health governance to com-
association between prescription drug abuse risks and social media not bat counterfeit medicines: a proposal for a UNODC-WHO-Interpol
related to this study. There was no involvement of anyone other than the trilateral mechanism. BMC Med. 2013;11:233.
authors in the conception, design, collection, planning, conduct, analysis, 17. Hamilton WL, Doyle C, Halliwell-Ewen M, et al. Public health inter-
interpretation, writing, and discussion to submit this work. The authors ventions to protect against falsified medicines: a systematic review
have no other relevant affiliations or financial involvement with any of international, national and local policies. Health Policy Plan. 2016
organization or entity with a financial interest in or financial conflict Dec;31(1):1448–1466.
with the subject matter or materials discussed in the manuscript apart •• A comprehensive review detailing various policy approaches
from those disclosed. to tackling fake medicines.
18. Dipika Bansal SMKGPT Anti-counterfeit technologies: a pharmaceu-
tical industry perspective. Sci Pharm. Österreichische Apotheker-
ORCID Verlagsgesellschaft, m. b. H. 2013 Mar 1;81(1):1.
19. Amon JJ Dangerous medicines: unproven AIDS cures and counter-
Tim K. Mackey http://orcid.org/0000-0002-2191-7833 feit antiretroviral drugs. Global Health. BioMed Central Ltd. 2008
Feb 27;4(1):5.
20. Newton PN, Green MD, Mildenhall DC, et al. Poor quality vital anti-
malarials in Africa - an urgent neglected public health priority.
References
Malar J. BioMed Central. 2011 Dec 13;10(1):352.
Papers of special note have been highlighted as either of interest (•) or of 21. Nayyar GM, Breman JG, Newton PN, et al. Poor-quality antimalarial
considerable interest (••) to readers. drugs in southeast Asia and sub-Saharan Africa. Lancet Infect Dis.
1. Mackey TK, Liang BA. The global counterfeit drug trade: patient 2012 Jun;12(6):488–496.
safety and public health risks. J Pharm Sci. 2011 Nov;100(11):4571– 22. Mackey TK, Liang BA, York P, et al. Counterfeit drug penetration
4579. into global legitimate medicine supply chains: a global assessment.
2. Jack A. Counterfeit medicines. Bitter pills. BMJ: british medical jour- Am J Trop Med Hyg. American Society of Tropical Medicine and
nal. Br Med J Publishing Group. 2007 Dec 1;335(7630):1120–1121. Hygiene. 2015 Jun;92(6 Suppl):59–67.
3. Growing threat from counterfeit medicines. Bull World Health •• This report is the first to analyze data on counterfeit medicine
Organ. 2010 Apr;88(4):247–248. penetrations in the global drug supply chain.
 EXPERT OPINION ON DRUG SAFETY 599

23. Nayyar GML, Attaran A, Clark JP, et al. Responding to the pandemic 42. Wertheimer AI, Norris J Safeguarding against substandard/counter-
of falsified medicines. Am J Trop Med Hyg. American Society of feit drugs: mitigating a macroeconomic pandemic. Res Social Adm
Tropical Medicine and Hygiene. 2015 Jun;92(6 Suppl):113–118. Pharm. Elsevier. 2009 Mar;5(1):4–16.
24. Nayyar GML, Breman JG, Herrington JE The global pandemic of 43. Karunamoorthi K The counterfeit anti-malarial is a crime against
falsified medicines: laboratory and field innovations and policy humanity: a systematic review of the scientific evidence. Malar J.
perspectives. Am J Trop Med Hyg. American Society of Tropical BioMed Central Ltd. 2014 Jun 2;13(1):209.
Medicine and Hygiene. 2015 Jun;92(6 Suppl):2–7. 44. Tabernero P, Fernández FM, Green M, et al. Mind the gaps–the
25. Wigand RT, Mande DM, Wood JD. Information management and epidemiology of poor-quality anti-malarials in the malarious
tracking of drugs in supply chains within the pharmaceutical indus- world–analysis of the worldwide antimalarial resistance network
try. Eighth International Conference on Information Technology: database. Malar J. BioMed Central. 2014;131:139.
New Generations. 2011;500–507. 45. Kovacs S, Hawes SE, Maley SN, et al. Technologies for detecting
26. QuintilesIMS. Global medicines use in 2020: outlook and falsified and substandard drugs in low and middle-income coun-
Implications. www.imshealth.com [Internet]. Nov 2015. Available tries. Sullivan DJ, editor. Plos ONE. 2014 Mar 26;9(3):e90601.
from: http://www.imshealth.com/en/thought-leadership/quintile •• A comprehensive review of existing technologies to combat
sims-institute/reports/global-medicines-use-in-2020. fake medicines that this study adds to.
27. Masoumi AH, Yu M, Nagurney A. A supply chain generalized net- 46. Coustasse A, Arvidson C, Rutsohn P Pharmaceutical counterfeiting
work oligopoly model for pharmaceuticals under brand differentia- and the RFID technology intervention. J Hosp Mark Public
tion and perishability. Trans Res Part E: Logis Trans Rev. 2012 Jul;48 Relations. Taylor & Francis Group. 2010 Jul;20(2):100–115.
(4):762–780. 47. Mackey TK, Liang BA. Pharmaceutical digital marketing and gov-
28. Taylor D. RFID in the pharmaceutical industry: addressing counter- ernance: illicit actors and challenges to global patient safety and
feits with technology. J Med Syst. 2014 Nov;38(11):141. public health. Global Health. 2013 Oct 16;9(1):45.
29. Bailey W Globalization of the Life Sciences Supply Chain. 48. Maxwell SRJ, Webb DJ. Internet pharmacy: a web of mistrust? Bjcp.
wwwpwccom [Internet]. January/February 2011. Available from: 2008 Aug;66(2):196–198.
http://www.pwc.com/us/en/health-industries/assets/pdf/globaliza 49. Montoya ID. The root cause of patient safety concerns in an
tion-of-the-life-sciences-supply-chain.pdf Internet pharmacy. Expert Opin Drug Saf. 2008 Jul;7(4):337–341.
30. Tremblay M. Medicines counterfeiting is a complex problem: a 50. Liang BA, Mackey T. Searching for safety: addressing search engine,
review of key challenges across the supply chain. Curr Drug Saf. website, and provider accountability for illicit online drug sales. Am
2013 Feb;8(1):43–55. J Law Med. 2009;35(1):125–184.
31. ISMP. Gray market, black heart: pharmaceutical gray market finds a 51. Mackey TK, Nayyar G Digital danger: a review of the global public
disturbing niche during the drug shortage crisis [Internet]. ismp. health, patient safety and cybersecurity threats posed by illicit
org. 2011 [cited 2011 Sep 26]. Available from: http://www.ismp.org/ online pharmacies. Br Med Bull. Oxford University Press. 2016
Newsletters/acutecare/showarticle.asp?ID=3 Jun;118(1):110–126.
32. Rosenthal ET The “gray market” raises concerns about cost, safety, •• Review article specifically outlines the unique challenges faced
and ethics. JNCI J Natl Cancer Inst. Oxford University Press. 2012 by illicit online pharmacies to drug safety.
Feb 8;104:168–170. 52. Liang BA, Mackey T. Direct-to-consumer advertising with interac-
33. Hemalatha R, Rao AS. Electronic solutions for combating counter- tive internet media: global regulation and public health issues.
feit drugs. J Pharm Bioallied Sci Medknow Publications. 2015 Jul;7 Jama. 2011 Feb 23;305(8):824–825.
(3):230–232. 53. Mackey TK, Liang BA. Global reach of direct-to-consumer advertis-
34. Mackey TK, Cuomo R, Guerra C, et al. After counterfeit Avastin – ® ing using social media for illicit online drug sales. J Med Internet
what have we learned and what can be done? Nat Rev Clin Oncol. Res. 2013;15(5):e105.
2015 May;12(5):302–308. 54. Orizio G, Merla A, Schulz PJ, et al. Quality of online pharmacies and
35. Cuomo RE, Mackey TK. An exploration of counterfeit medicine websites selling prescription drugs: a systematic review. J Med
surveillance strategies guided by geospatial analysis: lessons Internet Res. 2011;13(3):e74.
learned from counterfeit Avastin detection in the US drug supply 55. Ivanitskaya L, Brookins-Fisher J, O Boyle I, et al. Dirt cheap and
chain. BMJ Open. British Med J Publishing Group. 2014;4(12): without prescription: how susceptible are young US consumers to
e006657–7. purchasing drugs from rogue internet pharmacies? J Med Internet
36. Cuomo RE, Mackey TK, Stigler P. The economics of counterfeit Res. [Internet] 2010; 122. Available from: /pmc/articles/
Avastin: a geospatial and statistical analysis of demographic corre- PMC2885783/?report=abstract
lates to FDA warning letters. Pharmacoepidemiol Drug Saf. 2015 56. WHO. Safety and security on the Internet: challenges and advances
Jul;24(7):748–756. in member states [Internet]. WHO. 2011 [cited 2013 Mar 5]. Available
37. Kohler JC, Mackey TK, Ovtcharenko N. Why the MDGs need good from: http://www.who.int/goe/publications/goe_security_web.pdf
governance in pharmaceutical systems to promote global health. 57. Fittler A, Bősze G, Botz L. Evaluating aspects of online medication
BMC Public Health. BioMed Central Ltd. 2014;141:63. safety in long-term follow-up of 136 Internet pharmacies: illegal
38. Baghdadi-Sabeti G, Kohler JC, Wondemagegnehu E Measuring rogue online pharmacies flourish and are long-lived. J Med Internet
transparency in the public pharmaceutical sector: assessment Res. 2013;15(9):e199.
instrument [Internet]. apps.who.int. 2009 [cited 2013 Feb 26]. 58. Fadlallah R, El-Jardali F, Annan F, et al. Strategies and systems-level
Available from: http://apps.who.int/medicinedocs/documents/ interventions to combat or prevent drug counterfeiting: a systema-
s16732e/s16732e.pdf tic review of evidence beyond effectiveness. Pharmaceut Med.
39. Mackey TK, Kohler JC, Savedoff WD, et al. The disease of corrup- Springer International Publishing. 2016;305:263–276.
tion: views on how to fight corruption to advance 21(st) century 59. Kesselheim AS, Avorn J, Sarpatwari A. The high cost of prescription
global health goals. BMC Med Biomed Central. 2016 Sep 29;14 drugs in the United States: origins and prospects for reform. Jama.
(1):149. 2016 Aug 23;316(8):858–871.
40. Mackey TK, Liang BA. Combating healthcare corruption and fraud 60. Orizio G, Rubinelli S, Schulz PJ, et al. “Save 30% if you buy today.”
with improved global health governance. BMC Int Health Hum Online pharmacies and the enhancement of peripheral thinking
Rights. 2012;12(1):23. in consumers. Pharmacoepidemiol Drug Saf. 2010 Sep;19(9):970–
41. Nsimba SED. Problems associated with substandard and counter- 976.
feit drugs in developing countries: a review article on global impli- 61. Naughton B, Roberts L, Dopson S, et al. Effectiveness of medicines
cations of counterfeit drugs in the era of antiretroviral (ARVs) drugs authentication technology to detect counterfeit, recalled and
in a free market economy. East Afr J Public Health. 2008 Dec;5 expired medicines: a two-stage quantitative secondary care study.
(3):205–210. BMJ Open. 2016 Dec 9;6(12):e013837.
600 T. K. MACKEY AND G. NAYYAR

62. Li L. Technology designed to combat fakes in the global supply Chain Management and Information Systems (SCMIS), 2010 8th
chain. Bus Horiz. 2013 Mar;56(2):167–177. International Conference on 2010 Oct 6 (pp. 1–5). IEEE.
63. pwc. Digitization in pharma: gaining an edge in operations 82. Kaul SD, Awasthi AK RFID authentication protocol to enhance
[Internet]. strategyand.pwc.com. 2016 [cited 2017 Jan 30]. patient medication safety. J Med Syst. Springer US. 2013 Dec;37
Available from: http://www.strategyand.pwc.com/reports/digitiza (6):9979.
tion-in-pharma 83. Schapranow MP, Nagora M, Zeier A. CoMoSeR: cost model for
64. International Telecommunication Union. Press Release: ITU releases security-enhanced RFID-aided supply chains. InSoftware,
2016 ICT figures. [Internet]. 2016 [cited 2017 Jan 30]. Available Telecommunications and Computer Networks (SoftCOM), 2010
from: http://www.itu.int/en/mediacentre/pages/2016-PR30.aspx International Conference on 2010 Sep 23 (pp. 11–16). IEEE.
65. Isah H. Information and communication technology in combating 84. Choi JB, Rogers J, Jones EC. The impact of a shared pharmaceutical
counterfeit drugs. arxiv.org [Internet]. 2012. Available from: https:// supply chain model on counterfeit drugs, diverted drugs, and drug
arxiv.org/ftp/arxiv/papers/1211/1211.1242.pdf. shortages. InManagement of Engineering and Technology
66. Ur Rehman S, Ur Rasool RU, Ayub MS, et al. Reliable identification (PICMET), 2015 Portland International Conference on 2015 Aug 2
of counterfeit medicine using camera equipped mobile phones. (pp. 1879–1889). IEEE.
InHigh Capacity Optical Networks and Enabling Technologies 85. Nilsson E, Nilsson B, Järpe E. A pharmaceutical anti-counterfeiting
(HONET), 2011 2011 Dec 19 (pp. 273–279). IEEE. method using time controlled numeric tokens. InRFID-
67. Deus L Technological roles in combating drug diversion and coun- Technologies and Applications (RFID-TA), 2011 IEEE International
terfeiting. J Pharm Pract. Sage Publications. 2016 Jun 30;19(3):146– Conference on 2011 Sep 15 (pp. 343–347). IEEE.
152. 86. Alzahrani N, Bulusu N. Securing pharmaceutical and high-value pro-
68. Zedlmayer G mPedigree: a collective impact case study [Internet]. ducts against tag reapplication attacks using NFC tags. InSmart
ssir.org. 2011 [cited 2017 Jan 1]. Available from: https://ssir.org/ Computing (SMARTCOMP), 2016 IEEE International Conference on
articles/entry/mpedigree_a_collective_impact_case_study 2016 May 18 (pp. 1–6). IEEE.
69. You M, Zhong J, Hong Y, et al. Inkjet printing of upconversion 87. Yao X, Zhou X, Ma J. Object event visibility for anti-counterfeiting
nanoparticles for anti-counterfeit applications. Nanoscale. Royal in RFID-enabled product supply chains. InScience and Information
Soc Chem. 2015 Mar 14;7(10):4423–4431. Conference (SAI), 2015 2015 Jul 28 (pp. 141–150). IEEE.
70. Isa NM, Saaidin S, Sulaiman NA, et al. Pharmaceutical product 88. Carley LR, Colak G, Chomas L, et al. Technologies for secure RFID
information based on Android platform. InElectrical, Electronics authentication of medicinal pills and capsules. InRFID Technology
and System Engineering (ICEESE), 2014 International Conference and Applications (RFID-TA), 2016 IEEE International Conference on
on 2014 Dec 9 (pp. 66-70). IEEE. 2016 Sep 21 (pp. 10–15). IEEE.
71. Yu H, Le HM, Kaale E, et al. Characterization of drug authenticity 89. Kim H, Jeong H, Park H. A study on RFID/USN based e-pedigree
using thin-layer chromatography imaging with a mobile phone. J system for cold chain management. InTechnology Management
Pharm Biomed Anal. 2016 Jun;5(125):85–93. Conference (ITMC), 2012 IEEE International 2012 Jun 25 (pp. 137–
72. Yu H, Le H, Lumetta S, et al. Smartphone-based thin layer chro- 143). IEEE.
matography for the discrimination of falsified medicines. 90. Chen C, Zhang F, Barras J, et al. Authentication of medicines using
InSENSORS, 2016 IEEE 2016 Oct 30 (pp. 1–3). IEEE. nuclear quadrupole resonance spectroscopy. IEEE/ACM Trans
73. Jordan F, Kutter M. Identifying counterfeit medicines with industry- Comput Biol Bioinform. 2016 May;13(3):417–430.
suitable technologies. Pharmaceutical Engineering, The Offical 91. Rahman F, Ahamed SI. Looking for needles in a haystack: detecting
Magazine of ISPE. 2012 May;32(3). counterfeits in large scale RFID systems using batch authentication
74. Sinhal K. Soon, bar code & unique no. on pill strips to check fakes protocol. InPervasive Computing and Communications Workshops
[Internet]. 2011 [cited 2017 Jan 30]. Available from: http://timeso (PERCOM Workshops), 2012 IEEE International Conference on 2012
findia.indiatimes.com/india/Soon-bar-code-unique-no-on-pill- Mar 19 (pp. 811–816). IEEE.
strips-to-check-fakes/articleshow/7529728.cms 92. Schapranow M-P, Zeier A, Plattner H, et al. A formal model for
75. NAFDAC Nigeria Mobile Authentication Service (MAS) require- enabling RFID in pharmaceutical supply chains. InSystem Sciences
ments on anti-malarial & antibiotics [Internet]. pharmasecure.com. (HICSS), 2011 44th Hawaii International Conference on 2011 Jan 4
[cited 2017 Jan 30]. Available from: http://www.pharmasecure.com/ (pp. 1–10). IEEE.
NAFDAC%20Nigeria%20MAS%20Newsletter.pdf 93. Freifeld CC, Brownstein JS, Menone CM, et al. Digital drug safety
76. Shuaib H. A national ICT architecture for combating the counterfeit surveillance: monitoring pharmaceutical products in twitter. Drug
drug trade. www.academia.edu [Internet]. 2013. Available from: Saf. Springer International Publishing. 2014 Apr 29;37(5):343–350.
http://s3.amazonaws.com/academia.edu.documents/31545476/ 94. Salathé M, Bengtsson L, Bodnar TJ, et al. Digital Epidemiology.
Drug_anti-Counterfeit_Paper.pdf?AWSAccessKeyId= Bourne PE, editor. Plos Comp Biol. Public Library of Science. 2012
AKIAIWOWYYGZ2Y53UL3A&Expires=1490919434&Signature= Jul 26;8(7):e1002616.
7A8jNasDmFmZzluUKfIJmWBQBKU%3D&response-content-disposi 95. Hay SI, George DB, Moyes CL, et al. Big data opportunities for
tion=inline%3B%20filename%3DHaffiz_Shuaib_A_National_ICT_ global infectious disease surveillance. Plos Med. Public Library of
Architectur.pdf. Science. 2013 Apr 2;10(4):e1001413.
77. Ting SL, Kwok SK, Tsang AHC, et al. Critical elements and lessons 96. Katsuki T, Mackey TK, Cuomo R. Establishing a link between pre-
learnt from the implementation of an RFID-enabled healthcare scription drug abuse and illicit online pharmacies: analysis of twit-
management system in a medical organization. J Med Syst. ter data. J Med Internet Res. 2015;17(12):e280.
Springer US. 2011 Aug;35(4):657–669. 97. Kalyanam J, Katsuki T, R G Lanckriet G, et al. Exploring trends of
78. Huang GQ, Qin Z, Qu T, et al. RFID-enabled pharmaceutical regu- nonmedical use of prescription drugs and polydrug abuse in the
latory traceability system. InRFID-Technology and Applications Twittersphere using unsupervised machine learning. Addict Behav.
(RFID-TA), 2010 IEEE International Conference on 2010 Jun 17 (pp. 2017 Feb;65:289–295.
211–216). IEEE. 98. Obermeyer Z, Emanuel EJ. Predicting the future — big data,
79. Hall C. Technology for combating counterfeit medicine. Pathog machine learning, and clinical medicine. N Engl J Med. 2016 Sep
Glob Health. 2013 Nov 12;106(2):73–76. 29;375(13):1216–1219.
80. Yao X, Du W, Zhou X, et al. Security and privacy for data mining of 99. Adrover C. Identifying adverse effects of HIV drug treatment and
RFID-enabled product supply chains. InSAI Computing Conference associated sentiments using twitter. JMIR Public Health Surveill.
(SAI), 2016 2016 Jul 13 (pp. 1037-1046). IEEE. 2015;1(2):e7. JMIR Publications Inc., Toronto, Canada http://publi
81. Ting SL, Kwok SK, Albert HT, et al. Enhancing the information chealthjmirorg/2015/2/e7/
transmission for pharmaceutical supply chain based on Radio 100. O’Connor K, Pimpalkhute P, Nikfarjam A, et al. American Medical
Frequency Identification (RFID) and internet of things. InSupply Informatics Association. Pharmacovigilance on twitter? Mining
 EXPERT OPINION ON DRUG SAFETY 601

tweets for adverse drug reactions. AMIA Annu Symp Proc. 120. Mackey TK, Liang BA, Kohler JC, et al. Health domains for sale: the
2014;2014:924–933. need for global health internet governance. J Med Internet Res.
101. Lopes TJS, Shoemaker JE, Matsuoka Y, et al. Frontiers. Identifying 2014;16(3):e62.
problematic drugs based on the characteristics of their targets. 121. Mackey TK, Eysenbach G, Liang BA, et al. A call for a moratorium on
Front Pharmacol. 2015;6:186. the .health generic top-level domain: preventing the commerciali-
102. Zhao J, Henriksson A, Kvist M, et al. American Medical Informatics zation and exclusive control of online health information. Global
Association. Handling temporality of clinical events for drug safety Health. BioMed Central Ltd. 2014 Sep 26;10(1):62.
surveillance. AMIA Annu Symp Proc. 2015;2015:1371–1380. 122. Solomonides AE, Mackey TK Emerging ethical issues in digital
103. Isah H, Trundle P, Neagu D. Social media analysis for product safety health information. Camb Q Healthc Ethics. Cambridge University
using text mining and sentiment analysis. InComputational Press. 2015 Jul;24(3):311–322.
Intelligence (UKCI), 2014 14th UK Workshop on 2014 Sep 8 (pp. 123. Home - .Pharmacy [Internet]. safe.pharmacy. 2017 [cited 2017 Jan
1–7). IEEE. 30]. Available from: http://www.safe.pharmacy/
104. Voss EA, Boyce RD, Ryan PB, et al. Accuracy of an automated 124. Norton S. CIO Explainer: what Is Blockchain? [Internet]. blogs.wsj.
knowledge base for identifying drug adverse reactions. J Biomed com. 2016 [cited 2017 Jan 30]. Available from: http://blogs.wsj.
Inform. 2016 Dec;16(66):72–81. com/cio/2016/02/02/cio-explainer-what-is-blockchain/
105. Wang G, Jung K, Winnenburg R, et al. A method for systematic dis- 125. Mettler M. Blockchain technology in healthcare: the revolution
covery of adverse drug events from clinical notes. J Am Med Inform starts here. Ine-Health Networking, Applications and Services
Assoc. Oxford University Press. 2015 Nov;22(6):1196–1204. (Healthcom), 2016 IEEE 18th International Conference on 2016
106. Li A, Guo X, Xie J, et al. Validation of biomarkers in cardiotoxicity Sep 14 (pp. 1–3). IEEE.
induced by Periplocin on neonatal rat cardiomyocytes using UPLC- 126. Marr B. How blockchain technology could change the world
Q-TOF/MS combined with a support vector machine. J Pharm [Internet]. forbes.com. 2016 [cited 2017 Jan 30]. Available from:
Biomed Anal. 2016 May;10(123):179–185. http://www.forbes.com/sites/bernardmarr/2016/05/27/how-block
107. Drew J, Moore T. Automatic identification of replicated criminal chain-technology-could-change-the-world/
websites using combined clustering. InSecurity and Privacy 127. Harris P Rubix by deloitte on blockchain use cases for the pharma-
Workshops (SPW), 2014 IEEE 2014 May 17 (pp. 116–123). IEEE. ceutical supply Chain [Internet]. 2016 [cited 2017 Jan 30]. Available
108. Koepke J, Kaza S, Abbasi A. Exploratory experiments to identify fake from: /news/rubix-by-deloitte-on-blockchain-use-cases-for-the-phar
websites by using features from the network stack. InIntelligence maceutical-supply-chain/
and Security Informatics (ISI), 2012 IEEE International Conference 128. Shanley A Could blockchain enable secure data transfer? [Internet].
on 2012 Jun 11 (pp. 126–128). IEEE. 2016 [cited 2017 Jan 30]. Available from: http://www.pharmtech.
109. Mavlanova T, Benbunan-Fich R. What does your online pharmacy com/could-blockchain-enable-secure-data-transfer
signal? a comparative analysis of website trust features. InSystem 129. Taylor P Applying blockchain technology to medicine traceability
Sciences (HICSS), 2010 43rd Hawaii International Conference on [Internet]. 2016 [cited 2017 Jan 30]. Available from: https://www.
2010 Jan 5 (pp. 1–10). IEEE. securingindustry.com/pharmaceuticals/applying-blockchain-tech
110. Corona I, Contini M, Ariu D, et al. PharmaGuard: automatic identifica- nology-to-medicine-traceability/s40/a2766/
tion of illegal search-indexed online pharmacies. InCybernetics 130. Holmes B Blockchain Technology Battles Counterfeiting [Internet].
(CYBCONF), 2015 IEEE 2nd International Conference on 2015 Jun 24 bravenewcoin.com. 2015 [cited 2017 Jan 30]. Available from:
(pp. 324–329). IEEE. http://bravenewcoin.com/news/blockchain-technology-battles-
111. Abbasi A, Zahedi F, Kaza S. Detecting fake medical web sites using counterfeiting/
recursive trust labeling. ACM Trans Inf. 2012;30:1–36. 131. Allison I Chronicled launches blockchain-registered supply chain and
112. Der MF, Saul LK, Savage S, et al. Knock it off: profiling the online pharmaceutical packaging [Internet]. 2016 [cited 2017 Jan 30].
storefronts of counterfeit merchandise. the 20th ACM SIGKDD Available from: http://www.ibtimes.co.uk/chronicled-launches-block
international conference. New York, USA: ACM; 2014. p. 10. chain-registered-supply-chain-pharmaceutical-packaging-1592220
113. Lee HS, Bang HC. Detecting counterfeit products using supply 132. Del Castillo M Hyperledger project explores fighting counterfeit
chain event mining. InAdvanced Communication Technology drugs with blockchain [Internet]. 2016 [cited 2017 Jan 30].
(ICACT), 2013 15th International Conference on 2013 Jan 27 (pp. Available from: http://www.coindesk.com/hyperledger-counterfeit-
744–748). IEEE. drugs-blockchain/
114. Zikui L, Xuan G. The regulation model of pharmaceutical logistics 133. IEEE Launches World’s First Virtual Blockchain Workshop Dedicated
based on the supervision of flow. InLogistics Systems and to Advancing HealthTech for Humanity [Internet]. standards.ieee.
Intelligent Management, 2010 International Conference on 2010 org. 2016 [cited 2017 Jan 30]. Available from: http://standards.ieee.
Jan 9 (Vol. 2, pp. 1055–1059). IEEE. org/news/2016/virtual_blockchain.html
115. Banerjee S, Sweet J, Sweet C, et al. Visual recognition of paper 134. Blockchain for Pharma. Internet. 2017 [cited 2017 Jan 30]. Available
analytical device images for detection of falsified pharmaceuticals. from: http://beyondstandards.ieee.org/tag/blockchain-for-pharma/
InApplications of Computer Vision (WACV), 2016 IEEE Winter 135. The BlockRx Project [Internet]. blockrx.com. 2016 [cited 2017 Jan
Conference on 2016 Mar 7 (pp. 1–9). IEEE. 30]. Available from: http://www.blockrx.com/
116. NABP. VIPPS - national association of boards of pharmacy 136. Zadbuke N, Shahi S, Gulecha B, et al. Recent trends and future of
[Internet]. nabp.net. [cited 2011 Sep 21]. Available from: http:// pharmaceutical packaging technology. J Pharm Bioallied Sci. 2013
www.nabp.net/programs/accreditation/vipps/ Apr;5(2):98–110.
117. EU logo for online sale of medicines [Internet]. ec.europa.eu. 2016 137. Jamrógiewicz M. Application of the near-infrared spectroscopy in the
[cited 2016 Jan 11]. Available from: http://ec.europa.eu/health/ pharmaceutical technology. J Pharm Biomed Anal. 2012 Jul;66:1–10.
human-use/eu-logo/index_en.htm 138. Culzoni MJ, Dwivedi P, Green MD, et al. Ambient mass spectro-
118. LegitScript. Rogues and registrars: are some domain name regis- metry technologies for the detection of falsified drugs. Med Chem
trars safe havens for internet drug rings? [Internet]. [cited 2014 Jun Commun. Royal Society of Chemistry. 2014;51:9–19.
17]. Available from: http://www.legitscript.com/download/Rogues- 139. Pal SN, Olsson S, Brown EG The monitoring medicines project: a
and-Registrars-Report.pdf multinational pharmacovigilance and public health project. Drug
119. LegitScript. The-Internet-Pharmacy-Market-in-2016. Trends, Saf. Springer International Publishing. 2015 Apr;38(4):319–328.
Challenges and Opportunities. [Internet] [cited 2017 Mar 30]. 140. Fukuoka T, Yamaguchi A, Hara R, et al. Application of gold nano-
Available from: https://safemedsonline.org/resource/the-internet- particle self-assemblies to unclonable anti-counterfeiting technol-
pharmacy-market-in-2016-trends-challenges-and-opportunities/ ogy. InElectronic Packaging and iMAPS All Asia Conference (ICEP-
602 T. K. MACKEY AND G. NAYYAR

IACC), 2015 International Conference on 2015 Apr 14 (pp. 432– 142. Richards N, Hudson I. UK medicines regulation: responding to
435). IEEE. current challenges. Br J Clin Pharmacol. 2016 Dec;82(6):1471–
141. Das RN, Egitto FD, Lin H. Anti-counterfeit, miniaturized, and 1476.
advanced electronic substrates for medical device applications. In 143. Fayzrakhmanov NF. Fighting trafficking of falsified and substandard
Electronic Components and Technology Conference (ECTC), 2013 medicinal products in Russia. Int J Risk Saf Med. IOS Press.
IEEE 63rd 2013 May 28 (pp. 523–528). IEEE. 2015;27Suppl 1(s1):S37–40.