How can the problems caused by counterfeit medicines be

addressed?

Senior Sophister

Practice of Pharmacy Dissertation BSc.(Pharm)

Mena Eskander

11326931

Centre for the Practice of Pharmacy

The School of Pharmacy and Pharmaceutical Sciences

TRINITY COLLEGE DUBLIN

1

Table of Contents

Abstract................................................................................................................................. 2

Introduction ........................................................................................................................... 3

Methodology ......................................................................................................................... 6

Discussion ............................................................................................................................ 8

The consequences of pharmaceutical counterfeiting ......................................................... 8

Pharmaceutical trade and supply chain management ...................................................... 10

Technology in pharmaceutical industry ............................................................................ 12

Developing countries ....................................................................................................... 17

Online Pharmacies .......................................................................................................... 18

International collaboration: Essential but difficult ............................................................. 21

Conclusion .......................................................................................................................... 22

References ......................................................................................................................... 24

2

Abstract

The issue of pharmaceutical counterfeiting has a long history and has become significantly

more problematic in recent decades. Being necessarily clandestine, accurate estimation of

the size of the problem is difficult but is commonly accepted to range from <1% in the

developed world to over 30% in certain regions of the developing world. Opinions differ as to

the definition of counterfeit medicine, often as a result of the definition’s impact on legitimate

generic drug manufacturers and this hampers international collaborative efforts against the

issue and research. Though lifestyle drugs such as those used for erectile dysfunction are

amongst those most commonly targeted by counterfeiters, there has been an insidious

increase in the number of “life-saving” medicines being counterfeited such as anti-infectives,

anti-retrovirals and anti-neoplastics. It is recognised that the factors enabling counterfeiting

are numerous and that addressing the problems caused by counterfeit medicines will require

a complex and multi-faceted approach coordinated to include all relevant stakeholders. The

negative health consequences of these counterfeit medicines range from treatment failure to

severe and occasionally fatal toxicity. As no one country can produce all the medicines it

needs, pharmaceutical trade is global and complex involving a great number of

intermediaries in potentially convoluted and poorly managed supply chains. Tighter

management of these supply chains and implementing technological safeguards against

counterfeiting both in the supply chain and in products and/or their packaging deters

counterfeiters and secures the legitimate supply chain. The developing world and the

internet constitute two important markets of concern and are examined as case studies to

review possible approaches to address the problems caused by counterfeit medicines.

3

Introduction

It is difficult to estimate the scale of pharmaceutical crime and the counterfeiting of

medicines as it is inherently clandestine. Nonetheless, the impact of counterfeit medicines

use is significant and has led to negative outcomes ranging from treatment failure to death.

The definition of a “counterfeit medicine” has varied in the past according to each individual

state’s experience and perception of the problem. A common definition adopted by the WHO

(World Health Organisation) was agreed upon in 1992 to include any such medicine which is

fraudulently and deliberately mislabelled with regard to its identity and/or source. This

definition includes both branded and generic products with correct/incorrect or no active

ingredients. It also includes products with fake packaging and/or insufficient active

ingredient(s). [1] This differs very significantly from European Union’s definition of “counterfeit

medicine” (as in the ‘Falsified Medicines Directive’ 2011/62/EU) which refers only to

medicines which infringe on trademark law or intellectual property rights. In this particular

piece of EU legislation, the term “Falsified Medicine” aligns more closely to the WHO

definition of “counterfeit medicine” and includes products with falsified histories, especially

pertaining to their distribution channel. [2] For the purposes of this dissertation, the term

“counterfeit medicine” as defined by the WHO may be used interchangeably with the term

“falsified medicine” as defined by the European Union. It is also important to note the

distinction between a substandard medicine and a counterfeit medicine. Whilst counterfeit

medicines are invariably substandard, not all substandard medicines are counterfeit and it is

important that the two are not conflated and that the distinction is taken in to account when

defining the term “counterfeit medicine”.

Pharmaceutical crime is not a modern phenomenon. Though it has been identified as a

growing problem in recent decades, attempts to address falsified medicines date back to

antiquity with the Greek physician and botanist Dioscorides who advised how to identify such

products in his pharmacopoeia ‘De Materia Medica’. [1] Physicians, apothecaries and indeed

the general population of the past were cognisant of unscrupulous traders attempting to sell

substandard imitations of medicinal substances and many attempts were made in history to

combat this problem. One of the earliest such examples can be found in the 13th century in

the Constitutiones Imperiales of the Holy Roman Emperor Frederick II. The regulations are

notable for not only being one of the first to forbid physicians from co-practising as

apothecaries but explicitly required apothecaries to take an oath to prepare their medicines

without fraud. Apothecary inspectors to whom the enforcing of these regulations were

entrusted could be condemned to death should they have allowed fraud. [3] Most recently, in

1985, the issue began to be addressed on an international level with the WHO adopting

eradication of counterfeit medicines as one of its objectives.

Though attempts at eliminating pharmaceutical fraud and counterfeiting have been made

since ancient times, it is patently clear that no permanent progress has been made with the

counterfeit drugs trade estimated to be worth up to $200 billion with the death toll estimated

to be in the hundreds of thousands. [4] The WHO estimates that less than 1% (expressed as

percentage of market value) of pharmaceuticals in developed countries are counterfeit with

this figure rising very significantly in the developing world where estimates range from 10-

30%. [5] The range of problems caused by counterfeit medicines with regard to individual

patients is effectively limitless and ranges from treatment failure or reduced efficacy to fatal

4

toxicity depending on the nature of the counterfeit. Indeed, counterfeiters have not restricted

themselves to “lifestyle” drugs such as those used for erectile dysfunction as there have

been many reports of counterfeit “life-saving” drugs such as those used for the treatment of

infectious disease and cancer. Income lost by pharmaceutical industry – while it does act as

an impetus for manufacturers and legitimate traders in supply chains to implement anti-

counterfeiting measures – may also discourage research & innovation.

The rise of unregulated “online pharmacies”, greater accessibility of sophisticated

manufacturing and packaging equipment and the increasing base of experience of

counterfeiters have all contributed in some manner to both the increased availability and

purchase of counterfeit medicines.

There are a number of stakeholders with an interest in reducing the prevalence of

pharmaceutical counterfeiting. However, the perspective of each stakeholder differs towards

the issue and so too does their role in combatting the issue. Manufacturers, distributors,

pharmacies, drug regulatory authorities and consumers all have an interest and a different

role to play in combatting the counterfeiting of medicines.

According to statistics published in 2014, customs officials in the EU seized nearly 3.7 million

articles of falsified medicines and condoms in the preceding year with the number of falsified

medicines being seized by customs officials increasing every year. [6] Due to the highly

technical nature of some pharmaceutical products and increasingly sophisticated

manufacturing and packaging by counterfeiters, customs officials are finding it increasingly

difficult to detect counterfeit products during inspections and the European commission have

called for increased cooperation with pharmaceutical industry to help ameliorate the

situation. [7] A number of factors are associated with pharmaceutical counterfeiting such as

inadequate regulation and enforcement, lack of awareness amongst consumers and

professionals, complex multi-level distribution channels spanning international borders and,

at times, poor collaboration between stakeholders affected by counterfeit medicines. The

large price differential between authentic and counterfeit medicines also helps support the

counterfeit medicines market and particularly so in developing countries. [8]

An increase in transparency by pharmaceutical industry and increased governmental

reporting of pharmaceutical counterfeiting is important to facilitate combined efforts and

ensure adequate awareness of counterfeit medicines. Many investigations in to counterfeit

medicines in the past have been conducted in secret and any data obtained kept confidential

to the detriment of both public health and in many cases, drug manufacturers themselves.

Pharmaceutical industry should be legally obliged to disclose suspected counterfeiting of

their products to national drug regulatory authorities to ensure that state regulators are

cognisant of the quality of the pharmaceutical products present in the markets they regulate.

The necessity, potential risks and benefits of disseminating notice of counterfeiting to other

parties such as policymakers and general public should then be judged by the regulatory

authority prior to release to avoid potential harmful effects such an unnecessary loss of

confidence in legitimate therapeutic products. [9]

A successful anti-counterfeiting strategy should limit the number of counterfeit medicines

inadvertently reaching patients. Such strategies are not the sole responsibility of the drug

manufacturer and require the support of other stakeholders to be successful. A combined

effort by all interested parties will be most effective and ideally, will include; legislation and

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enforcement against those involved in counterfeiting, incorporation of technological

countermeasures both in products and through the supply chain and appropriate education

of all those involved in medication supply and use. In a 2015 systematic review of

interventions to combat and prevent drug counterfeiting, though it was noted that the quality

of studies included were inconsistent, it appeared that strong regulatory oversight and

collaborative, multi-faceted approaches in particular were effective at reducing the presence

of counterfeit medicines on the market. [10] As such, it is clear that a combination of

measures must be taken to address the problems caused by counterfeit drugs and these will

be further explored and appraised.

6

Methodology

In many cases, search engines such as Google were used to retrieve sources. When this

proved insufficient, electronic databases such as Embase or PubMed were used to source

articles. Limits, when necessary, were used to filter irrelevant results and to help localise the

results (where appropriate) to studies carried out in a particular country. In general, relevant

material was found within the first twenty results of each search with preference for the

websites of national and international authorities and articles published in peer-reviewed

journals as opposed to grey literature. Following appraisal, preference was afforded to

sources that were most relevant, most recent and with the least risk for bias. Sources that

were not publicly accessible were retrieved using the electronic library and database

services of Trinity College, Dublin.

Source Search Terms Limits No. Results No. Used

Google “definition” counterfeit medicine

Must contain the term “definition”

89,500 2

Google history of counterfeit medicines "medieval"

Must contain the term “history”

8,780,000 1

Google Counterfeit medicines “statistics”

Must contain the term “statistics”

48,000 4

Google Eudralex falsified medicines

2060 1

Google EU Customs “counterfeit” OR “falsified” AND “medicines” OR “pharmaceuticals” medicines

Must contain the term “counterfeit” or “falsified” and “medicines” or “pharmaceuticals”

299,000 2

Google US customs “counterfeit” “medicines”

Must contain the terms “counterfeit” and “medicines”

356,000 1

Google “consequences” counterfeit drugs

Must contain the term “consequences

152,000 3

Google “Viagra” counterfeit

Must contain the term “Viagra”

413,000 1

Embase Counterfeit Viagra

138 1

Google “problems” counterfeit medicines

Must contain the term “problem”

268,000 3

Google Avastin “Egypt” counterfeit

Must contain the term “Egypt”

6,520 2

Google EU GDP good distribution practice

214,000 2

Google “Parallel” import trade counterfeit

Must contain the term “parallel”

42,200 2

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medicine drugs

Google anti-counterfeiting technology pharmaceuticals medicines

293,000 6

Google RFID 2D Barcode medicines pharmaceuticals counterfeiting

25,900 2

Google mPedigree impact

52,000 1

Google GSM phone penetration “Africa”

Must contain the term “Africa”

286,000 1

Google China India penalty for counterfeit medicines

191,000 2

Google Online pharmacy counterfeit fake

368,000 1

Google Online pharmacy Ireland survey

Only results from Ireland

72,800 1

Google Online pharmacy quality survey counterfeit

383,000 1

Google “The Counterfeiting Superhighway”

22,400 1

Google Online pharmacy “common” logo

3,400,000 1

Pubmed Interventions counterfeit medicine

204 1

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Discussion

The consequences of pharmaceutical counterfeiting

Counterfeit medicines have a significant human and economic impact that is felt much more

widely than the balance sheets of drug manufacturers and patent holders.

Notwithstanding the waste of consumer income, counterfeit medicines also pose a very

serious risk to the health and safety of those who use them. Lifestyle drugs such as Viagra

(sildenafil) and other phosphodiesterase type 5 inhibitors such as Cialis (tadalafil) are used

to treat erectile dysfunction. Patients suffering from erectile dysfunction can often be

embarrassed and anxious with regard to their condition and this issue, in combination with

the relatively high price of these medicines, is why many consumers seek out more discreet

and/or cheaper routes of supply such as online pharmacies of dubious legitimacy. [11] In a

study funded by Pfizer where 22 online pharmacies selling Viagra were identified, 17 of

these pharmacies were found to supply counterfeits. Although the study concludes that 77%

of internet sites claiming to sell authentic Viagra actually sell counterfeit products, the

sample size of online pharmacies used is most likely much too small to make this assertion.

In addition, the distinct absence of well-established and legitimate online pharmacies from

the study such as pharmacy2u.co.uk and chemistdirect.co.uk is unusual and may suggest

that the results of this study may not be wholly accurate or reliable. [12] Nonetheless, it is

reasonable to say that many online pharmacies and particularly those that do not require a

prescription sell counterfeit medicines. In an attempt to address the privacy concerns of

patients, Pfizer has employed an innovative direct-to-consumer sales model for Viagra in the

United States in an effort to recover sales from other illegitimate online vendors and protect

patients and their brand. [13] While treatment failure in the context of erectile dysfunction is

unlikely to pose any serious negative health outcomes, counterfeit drugs treating this

condition have in the past led to serious negative outcomes including death. The New

England Journal of Medicine reported of severe hypoglycaemic episodes in a number of

patients taking counterfeit tadalafil. These counterfeits were contaminated with high

quantities of the sulfonylurea glyburide which when inadvertently taken by non-diabetics may

reduce serum glucose levels to the point of neuroglycopenia and possible coma. In this

particular instance, seven patients became comatose and four patients died from use of the

counterfeit product. [14] A wide variety of products have been counterfeited including

vaccines for avian flu [15], a number of different diagnostic tests such as lactate test strips

with falsified expiry dates [16] and fake HIV antibody testing kits. [17] Failure of vaccines and

diagnostics are equally if not more concerning as both are essential tools in public health

both being heavily relied upon in the prevention and management of communicable

diseases.

It is not just lifestyle drugs that have been targeted by counterfeiters. While treatment failure

in itself is of little serious long-term consequence in the context of lifestyle medicines such as

those for erectile dysfunction, particularly dangerous examples of counterfeit anticancer and

anti-infective drugs exist where treatment failure may lead to severe negative health

outcomes for patients. Counterfeits of the anti-VEGF biological drug Avastin (bevacizumab)

which is used to treat certain metastatic cancers and ocular diseases such as diabetic

retinopathy were found to contain salt, starch and a number of other substances such as

citrate, benzoic acid and acetone at varying levels but no active ingredient. The counterfeits

were detected in the US and were traced through a number of legitimate US, EU and Swiss

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suppliers all the way back to the Middle East with the most likely point of origin being Egypt. [18, 19] Notwithstanding the consequences of treatment failure, the potential toxicity posed by

injection of these chemicals and probable lack of sterility in combination with the fragile state

of the patient cohorts that Avastin is most commonly administered to makes for a particularly

dangerous combination.

The risks posed by counterfeit medicines to consumers and patients are limitless.

Malevolent counterfeiters with little regard for safety have in the past used toxic solvents

such as diethylene glycol (as implicated in the “Elixir sulphanilamide disaster” of 1937 which

served as a lesson for legitimate producers) for the preparation of paediatric paracetamol

syrup, turmeric in lieu of ampicillin, contraceptives containing wheat flour rather than

hormones, injectable vaccines and neomycin eye drops composed of non-sterile tap water

and an assortment of anti-infectives including antimalarials containing no active ingredient. [20]

In addition to the direct negative health outcomes that individuals who have used counterfeit

medicines may experience, the presence of counterfeits may cause uncertainty and doubt

amongst patients as to the value of the genuine drug. The effects of this are twofold.

Prescribers and patients may elect to use alternative and possibly less-effective therapies

and sales of the genuine drug will suffer as a result. As such, it is therefore clear that

patients, prescribers and pharmacists have much to lose from counterfeit medicines and all

have an interest in their removal from the market. Leaving aside their deleterious effects on

public health, counterfeit medicines pose a significant issue worthy of attention for the

governments of countries in which the legitimate version of these medicines are

manufactured due to the potentially significant loss of tax revenue. This is also an issue

where counterfeit medicines are sold as these illicit traders are likely to conceal their sales

from government.

From a financial standpoint, the pharmaceutical industry including both manufacturers and

distributors are among those with most to lose. Sales revenues which can be used to fund

further drug development constitutes a direct loss. However, pharmaceutical industry also

suffers a number of indirect losses due to counterfeit medicines. Pharmaceutical companies

must employ sophisticated anti-counterfeiting measures to protect intellectual property and

the reputation of their products.

Though the financial consequences of counterfeiting medicines are not unique in the greater

context of counterfeit goods, the severe risk that counterfeits pose to health makes

pharmaceutical counterfeiting a particularly odious and morally repugnant crime.

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Pharmaceutical trade and supply chain management

Being necessarily a global market, trade in pharmaceuticals is highly complex with

significant governmental involvement and ideally, a high degree of regulatory oversight.

Despite the fact that the health systems of all countries may require access to almost all

pharmaceuticals, there is no country that manufactures all pharmaceuticals and as such

importation of either the active pharmaceutical ingredient or finished product is necessary.

It is therefore not surprising that drugs are often obtained through highly complex distribution

channels involving multiple intermediaries (who may legitimately repackage/re-label

medicines) and countries. This provides many avenues through which counterfeit products

may enter and compromise legitimate channels and also presents opportunities for

counterfeiters to obfuscate the origin of their products. It is therefore imperative that strict

controls are in place to detect and deter the import and export of counterfeit medicines.

According to statistics published by US Customs & Border protection, nearly $80 million

(valued at the manufacturer’s RRP) worth of counterfeit pharmaceuticals were seized in the

United States in 2,215 seizures in 2013. [21] Over 3 million articles of counterfeit medicines

were seized at EU borders in 1,175 seizures. [6]

Manufacturers have a responsibility to ensure their products are distributed through a

controlled and high-quality network and users/retailers of medicines such as hospital and

community pharmacies have a responsibility to ensure to only procure their medicines

through legitimate channels.

As previously discussed, pharmaceutical trade is global and it must be acknowledged that

aside from exceptional cases of manufacturers selling direct-to-consumer, products are

delivered from manufacturer to customer through a complex chain of interactions between

companies. As counterfeits may infiltrate the supply chain at any point, any supply chain is

only as good as its weakest link and it is likely that proactive measures to prevent the entry

of counterfeit medicines in to the chain will be most effective in reducing the number of

counterfeit medicines reaching consumers.

In the EU, the principles of Good Distribution Practice (GDP) are outlined in guidelines

supported by article 10 of council directive 92/25/EEC. [22] These guidelines stipulate a

number of requirements that wholesalers and indeed other intermediaries in pharmaceutical

distribution channels should meet to ensure GDP. An appropriately qualified individual

(“responsible person”) must manage each distribution point with defined authority and a

responsibility to implement and run a system to ensure quality. This quality management

system is comprehensive and does not focus exclusively on counterfeit medicines. With

regard to protecting the supply chain from counterfeits, GDP implementation is multi-faceted

and key points to be highlighted on each facet include

Personnel

Key personnel involved must have sufficient skill/experience and all personnel must

be adequately trained for their role, with such training being recorded to assure its

completion. Training specific to the detection and handling of falsified medicines is

required.

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Documentation

All documentation should be provided on request of a competent authority to facilitate

investigation.

Orders placed with wholesalers must be addressed only to individuals authorised to

supply medicinal products as wholesalers or holders of manufacturing/importing

licenses. Wholesale orders should not be placed from unauthorised sources.

Standard operating procedures (SOPs) must be drafted to explicitly describe all

procedures which are important for the quality of products being distributed such as

storage, maintenance of premises, withdrawal and quarantine, record-keeping,

security of stock on site and shipping amongst many other operations. All such SOPs

must be assigned by the individual responsible for quality management system. This

is to reduce varied practice between personnel and ensure standard practice with

largely predictable and controlled outcomes.

Appropriately detailed records must be made during each operation and be kept

available for at least five years. Records of purchases and sales must also be kept

with certain details (such as batch number) being specified to ensure traceability of

products to facilitate investigations of counterfeiting and recall.

Premises and equipment

Products received should be inspected and any of those with damaged tamper-

evident packaging features and/or otherwise is suspected of being counterfeit should

be quarantined so as to prevent their sale or contamination of other goods.

Deliveries to customers

Medicinal products should be transported in a manner so to ensure that they are

protected from theft and diversion

Emergency plans and recalls

Emergency plans for urgent recalls should be detailed in writing with a specific

individual being designated responsible for coordination and execution of the plan.

Records must be made at the time of execution of the plan and these must be

distributed to the competent authorities of states where the products were distributed.

The purpose of recording to whom was delivered which product(s) is to ensure that

wholesalers may be able to identify and contact their customers in the event of a

recall.

Counterfeit products identified in the channel must be quarantined and clearly

labelled as unsaleable. Both the competent authority and marketing authorisation

holder of the authentic product must be immediately informed. [23]

However, GDP in the EU is governed primarily by “soft laws” such as guidelines and it is

debateable if this is sufficient. Though legal in the EU, particular concerns have also been

raised about the risks posed by parallel import distribution channels as these introduce a

number of complexities in to the legitimate supply chain which affords counterfeiters further

opportunities to bring their goods to market. Conventional distribution could be as simple as

a manufacturer who supplies to a mainline distributor/wholesaler who subsequently supplies

to pharmacies. Parallel imports however may have an artificially high number of

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intermediaries with brokers, repackaging agents and couriers interspersed in to the chain.

Parallel imports often must be repackaged to meet the legal and regulatory requirements of

their country of sale. Packaging must be translated and the details presented must

correspond to the license of the state in which they are to be sold. In addition, some parallel

importers assign new batch numbers to products during repackaging. These measures may

cloud manufacturer’s attempts to include anti-counterfeiting technology in their packaging

and make it more difficult to trace the origin of a batch. Where repackaging involves

complete replacement of the drug’s packaging, appropriate measures must be in place to

avoid the original packaging falling in to the hands of counterfeiters and this cannot be

guaranteed. Directive 2011/62/EU requires that all parallel importers verify the authenticity of

their goods but must replace any security devices with a device equivalent to that of the

original packaging should any of these features be rendered inoperable during the

repackaging process. [24] Though the European Alliance for Access to Safe Medicines is

funded primarily by innovative companies who stand much to lose financially from parallel

trade, there has been significant cause for concern with regard to some aspects of parallel

trade and increased risk of counterfeit products reaching the market due to the increased

number of stakeholders involved and varying levels of adherence to good manufacturing and

distribution practice. [25]

Technology in pharmaceutical industry

In response to the growing problem of pharmaceutical counterfeiting, manufacturers and

rights holders are increasingly turning to the investigation and use of new technologies to

safeguard against counterfeiting. Perhaps the simplest of these methods is the use of

tamper-evident packaging such as shrink wrap and breakable seals to provide consumers

with assurance that the product has not been altered since production. This is however

easily overcome by counterfeiters and though useful as a component of a multi-faceted anti-

counterfeiting strategy, is unlikely to offer much assurance to consumers on its own. [26]

A number of other anti-counterfeiting technologies exist and these revolve around product

authentication or tracing.

Product authentication and traceability

A number of technologies exist for manufacturers to uniquely mark their products and/or

their products’ packaging as an assurance of authenticity. In the EU, the Falsified Medicines

Directive 2011/62/EU mandates that all products must have a security feature suitable for

authentication present on their outer packaging. [2] The success of these techniques is

dependent on many factors. In order to successfully deter counterfeiting:

The authentication mark or feature must be sufficiently complex as to be technically

challenging to produce a clone of sufficient similarity to deceive.

The authentication mark must be placed on either the dosage form or its packaging

in such a manner that legitimate packaging cannot be re-used by counterfeiters.

Education must be provided so as to ensure the authentication mark is easy to use

for consumers and others who may have reason to verify the product’s authenticity.

Incorporation of the authentication mark should not adversely affect the product or its

packaging.

Incorporation of the authentication mark must be economical.

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Overt and visible features such as holograms, optically variable devices, colour-shifting

security inks and films, security graphics, sequential numbering and on-product marking are

targeted for the most part at consumers and others who may require to quickly authenticate

a product without use of specialist equipment. These features are prominently visible and

necessarily must be difficult and/or expensive to reproduce. Many of these features such as

holograms have been compromised as the technology used in their manufacture is well-

documented and sufficiently affordable for all but the smallest of counterfeiting operations. [27] Each of these solutions have their own unique advantages and disadvantages. In

general, overt markings can potentially by verified by end users with appropriate education

but have the disadvantage of being relatively easy to overcome by counterfeiters.

Notwithstanding the possibility of counterfeiters mimicking visible authentication marks, the

assurance offered by visible marks may be easily compromised if the mark is located on an

area of packaging that is unaffected by opening of the package. It is for this reason that

manufacturers are recommended to combine visible security features with tamper-evident

elements of the packaging such as security seals. [28]

“Simple” holograms designed for use by end-users may be easily defeated as counterfeiters

need not produce a 1:1 copy of the genuine hologram. Indeed, the mere presence of a

hologram is enough to deceive the casual observer and in many cases the differences

between a counterfeit and genuine hologram may be so minute as to require highly technical

analysis requiring knowledge and a trained eye. [29] As such, while increasing complexity of

holograms may make their imitation more challenging for counterfeiters, this is uncertain to

translate to improved recognition of the genuine hologram by consumers. A number of

innovations have been made in recent years and in particular with the incorporation of covert

features in to holograms to allow for both authentication by end-users and the drug

manufacturer.

Covert features are inconspicuous and intended for use by the rights owner of the product to

verify its authenticity. The details of these features are necessarily kept obscure and out of

the public domain as their public knowledge may compromise their security value. As

mentioned previously, covert features may be located on overt security features to add a

further hidden layer of complexity. Such features include:

Printing using “invisible” inks which require UV or IR illumination to be visualised and

may be formulated to fluoresce at different wavelengths (different colours) when they

are irradiated using different wavelengths of light. This is not always challenging for

counterfeiters to overcome as such inks (or similar inks) are widely available and

easily formulated by determined counterfeiters. The use of thermochromic inks which

change colour on heating is also possible. Infrared-absorbing inks, while expensive,

may offer a high degree of security as certain formulations are based on closely held

intellectual property with the detectors required for their reading being highly

sensitive. [30]

Printing of microtext which may require magnification to be visualised (semi-covert)

Encoded features which require specialised viewers for their deciphering and

viewing. An example of this is the Holospot produced by tesa scribos, a proprietary

solution which offers multiple overt and covert security features in one package. This

has the advantage of being easy to adopt by brand owners and manufacturers but

14

the disadvantage of being easier to compromise due to potentially widespread

adoption. [31]

RFID (Radio-frequency identification) tagging is a relatively widely used technology

that is becoming more commonly adopted in the pharmaceutical sector as a covert

security feature. Products or their packaging are tagged with a tag or label which at

minimum consists of an integrated circuit controller and a radio-frequency antenna.

This is sufficient for a passive RFID tag which is powered by the signal transmitted by

the reader (a transceiver). Active RFID tags have much larger range than passive

tags but this and their more complicated circuit design adds cost and increases the

size and visibility of the tag. As such, passive RFID tags are more suitable for covert

inclusion in pharmaceutical packaging as these can be inconspicuously incorporated

in packaging materials. [32]

RFID tags in particular are an attractive option as they are potentially multifunctional. Not

only can the tags be used for verifying product authenticity but they can be used to store

data on the product such as its serial number, batch number and site of production. In

addition, with an appropriate reader device, RFID tags may be used to facilitate traceability

of medicines throughout the lifecycle of the product in the supply chain from manufacturer to

pharmacy. With regard to serial numbers, the EU has mandated that all pharmaceutical

manufacturers serialise their products before 2017. [2] Tracking of medicines requires each

saleable unit of the product to be serialised so as to provide a unique identifier. Many

pharmaceutical manufacturers serialise their products in accordance to the industrial

standards set by GS1 with a sGTIN (serialised global trade item number) which is comprised

of a unique identification number for each product to which is appended a unique serial

number for each unit of the product. [33] While the implementation of serialisation and track

and trace technology is expensive and potentially complicated if records are created at each

transaction from the manufacturer through the supply chain to the pharmacy, the myriad

benefits may make it a worthwhile investment for certain medicines at high risk of

counterfeiting or whose counterfeiting may seriously compromise public health or the

commercial viability of an innovative medicine. Having such detailed traces of a product’s

path through the supply chain also greatly simplifies the process of recall should the need

arise. It is however important to keep in mind that counterfeiting is most significant as an

issue in developing countries where manufacturers must be highly conscious of consumer

spending power and state budgets for healthcare. The increase in cost associated with

expensive anti-counterfeiting technologies may increase the price differential between the

authentic and counterfeit product to such an extent that the authentic product is no longer

affordable. This is of course counterproductive as it not only deprives patients of the genuine

therapeutic product but leads to lost revenues to a similar if not greater extent than that

caused by counterfeit products. [34] As such, for anti-counterfeiting technology to be truly

effective, it is imperative that manufacturers strike the right balance of security and

affordability. RFID tagging is somewhat more expensive ($0.20-0.50 per tag) in comparison

to other technologies such as 2D barcodes ($0.02 per barcode). [35] In addition, regardless of

how tagging is implemented in packaging, there must be appropriate infrastructure

throughout the supply chain to support the system.

Linear or one-dimensional barcodes encode data by varying the spacing and widths of

parallel lines. Matrix or two-dimensional barcodes, which may store more data per unit area,

encode data in a two dimensions using a variety of shapes and/or colours. A number of

15

standards exist such as the QR (quick response) code originally developed for the Japanese

automobile industry which encodes data using black square pixels, PDF417 and data matrix

which is in the public domain and uses open-source software. A schematic describing the

four aforementioned barcode types may be viewed in Figure 1. [36] RFID tags may be

scanned without the necessity of close proximity or line-of-sight between the tag and the

reader. This may make them susceptible to interference and may introduce some concerns

of privacy for consumers. However this same characteristic offers the advantage of

permitting bulk scanning. As previously outlined, there is a significant difference in cost

between the two technologies and this makes 2D barcoding a particularly suitable option in

highly price-sensitive products and/or markets. RFID tags may also theoretically be

multifunctional incorporating features such as temperature monitoring as required for

assuring the integrity of cold chain products. [37] In a comparison of the two technologies, the

following were noted as advantages and disadvantages of the two technologies and these

are summarised in in Table 1. [38]

Figure 1

Table 1 A comparison of RFID and 2D Barcodes

Technology RFID 2D Barcode

Line of sight required No Yes Covert Possible No Susceptible to interference Yes No Support for bulk scanning Yes No Cost per unit tagged High Low Initial set up cost High Low Data density High Low Multifunctional Possible No Forgery and duplication Difficult Easy

RFID tagging is more sophisticated and versatile in terms of its capabilities yet is more

expensive and is currently not widely adopted. It is therefore perhaps more suitable for high-

16

value products where the cost of implementing the technology will not significantly increase

the cost price of the product. Some disadvantages of 2D barcoding such as the requirement

to scan each individual product unit may be overcome by hierarchical systems where

scanning of the shipping package identifies the contents of the shipment. For tracking and

tracing to be successful, it will be necessary for all those involved in distribution from

manufacturer to pharmacies to invest in the necessary equipment. Widespread adoption is

unlikely if a number of competing technologies are used by a variety of manufacturers and

as such a universal system of tracking medicines may be desirable. In a report by IMPACT,

it was recommended that an industry-wide working group be established to develop

harmonised data and database infrastructure specifications as well as discuss principles of

ownership, management and access of any tracking databases. It is also recommended that

industry proceeds initially with 2D barcodes as they are more affordable and may be easier

to implement with an eye to transitioning to RFID in the future. [28]

Another class of covert security features are those known as forensic markers. These are

similar to other covert features in that their presence and testing methods are kept obscure

but the difference lies in that their testing methods require the use of specialist testing in a

laboratory setting using sophisticated or specialist testing equipment such as electron

microscopes. They are most commonly used to provide evidence of counterfeiting in legal

proceedings against counterfeiters as routine analysis is inefficient and difficult. Mixing of

different forensic markers in defined proportions may create a fingerprint that is difficult if not

impossible to reverse engineer by counterfeiters. A number of possible markers include:

Isotopic tags (e.g. using a defined mixture of 13C/12C or tagging certain moieties with 13C rather than 12C in drug molecules). This feature may only be detected using mass

spectrometry and is quite difficult to replicate by counterfeiters.

DNA Markers comprised of a short synthetic sequence of nucleotide bases are

included in security labels and security inks. Pens which contain the complementary

chain of nucleotide bases tagged with a moiety which fluoresces on base-pairing

allows for portable testing. Alternatively, when the concentration of DNA marker is

very low, the use of techniques such as polymerase chain reaction (PCR) may be

used to amplify the marker for analysis.

Similarly to DNA marking, antibody-based systems rely on the pairing of an

antibody in the testing kit to its antigen (which acts as the marker in the product).

While this is highly sensitive, exceedingly difficult to counterfeit and with a low risk of

false-positive test results it is rather expensive and requires refrigeration of the

testing kit to prevent protein degradation of the antibody. [30]

Micro-taggants are particles of microscopic size of such characteristics or arranged

in such a manner as to act as a unique identifier for a product when examined under

a microscope. For example, a string of text may be depicted in small threads of

particles in a signature colour combination. [28]

Though technology plays an important role in anti-counterfeiting strategies, it cannot replace

due diligence by those involved with supply of medicines such as pharmacists and vigilance

by consumers.

17

Developing countries

Counterfeit pharmaceuticals are most significant of an issue in developing countries in Africa

and Asia. Non-existent or lax drug regulatory authorities, corruption and poor economic

development has created ideal conditions for counterfeiters to manufacture their products

and sell them to consumers with little difficulty or deterrent.

Counterfeit medicines are particularly prevalent in Sub-Saharan African countries with

estimates that up to 700,000 people die in Africa each year as a result of counterfeit

medicines for tuberculosis and malaria. While it is sensationalist to call this mass murder as

it cannot be guaranteed that the authentic medicine would’ve been affordable, available

and/or efficacious, there is no doubt that pharmaceutical counterfeiting is morally odious and

heinously criminal. In 2009, the United Nations Office on Drugs and Crime reported that

$438 million worth of antimalarials corresponding to 45 million doses were sold in West

Africa by manufacturers based in China and India. This figure exceeds the GDP of some

African nations such as Guinea-Bissau. The loss of tax revenue from counterfeiting is also

problematic for many countries with estimates in the hundreds of millions. Notwithstanding

fatalities, the impact on public health is also devastating with counterfeit anti-infectives

allowing for the spread of communicable diseases and the growth of resistance. [39]

Corruption, ineffective legislation and enforcement, lax regulatory control, expensive

authentic medicines and chaotic, uncontrolled drug distribution have all been cited as major

contributing factors to the high prevalence of counterfeit medicines in this region. In Nigeria,

addressing corruption and improving efficiency of the nation’s drug regulatory body has been

claimed to have helped reduce the circulation of counterfeit products by 80% over the space

of five years. [40]

In many countries in Sub-Saharan Africa and Asia, an innovative pedigree tracing system

(mPedigree) that offers consumers a convenient and accessible way to verify the

authenticity of their medicines has proven highly successful to the point that it has been

adopted as a regional standard by the West African Health Organisation. Participating

pharmaceutical companies generate a unique serial number for each product unit which is

then printed and obscured under a scratch-to-view panel. A database containing these

unique identifiers and the product details to which they refer is maintained centrally and

consumers may check the authenticity of their item by texting a toll-free number. [41]

Notwithstanding the risk of corrupt practices and/or unauthorised access and modification of

the central database, this system is difficult to compromise by all but the most determined

counterfeiter. In addition, with the GSM association predicting that mobile phone penetration

in Sub-Saharan Africa is nearing 80%, the fact that all that is required for end-users to use

the service is a feature phone is a major advantage. [42]

China and India are notable not only for being the source of a great number of counterfeit

medicines but also for being hubs of legitimate pharmaceutical manufacturing with a

fledgling export market. According to the World Trade Organisation, in China and India,

pharmaceutical exports were valued at approximately 12 and 13 billion respectively in 2013-

2014 with India showing the largest growth in exports of all regions with established

pharmaceutical industry. [43] The presence of counterfeit manufacturers in these countries

tarnishes the reputation of their legitimate counterparts and may be hampering the growth of

legitimate pharmaceutical exports from these countries. As such, both countries have

18

introduced a number of measures to stem the production of counterfeit medicines in their

respective territories.

In 1999, the WHO published a comprehensive (at the time) set of guidelines as to how

governments and state drug regulatory authorities (DRA) may combat pharmaceutical

counterfeiting. These include political commitment and the promulgation of appropriate

legislative controls and legal penalties that are kept up to date with changes in the issue.

Countries without a DRA were recommend to established. Those in which a DRA was

already established were recommended to ensure their power was independent and

sufficient to detect and control counterfeit drugs on the market. Importance was placed on

collaboration both on a domestic and international level by ensuring that all stakeholders are

appropriately educated on the nature of the issue and are aware of their roles and

responsibilities in combatting counterfeit medicines. In addition, it was recommended that

countries empower their judiciary to promptly process cases of counterfeiting and impose

severe penalties corresponding to the immorality of pharmaceutical counterfeiting and the

exceptional danger counterfeits pose to health. [44] The Indian government introduced the

death penalty for the manufacturers and sellers of counterfeit drugs but later reduced the

penalty to life imprisonment. [45] The Chinese judiciary may also impose very harsh

sentences such as the death penalty for those convicted of drug counterfeiting. Indeed, in

2009, China executed a number of traders exporting counterfeit antimalarials with a fake

“Made in India” label. [46] Earlier in 2007, the former director of the Chinese State Food and

Drug Administration was executed for corruption and accepting bribes that allowed for the

release of a number of untested, substandard products that caused both harm and death. [47]

It is questionable however if these very severe penalties are effective as a deterrent.

Online Pharmacies

The internet has without doubt changed society. The manner in which humans interact with

one another has changed irreversibly with the technology having bridged gaps across the

world as no other technology that preceded it.

Research by Nielsen estimated that online business to consumer sales reached $1.5 trillion

in 2014, corresponding to a 20% increase in sales from 2013. [48] A survey of over 6,000

Americans who had bought something on the internet before was conducted by the FDA and

identified that while 23% of the sample group had bought prescription medicines online, 29%

reported they were unsure as to how one may safely buy medicine on the internet. 15%

reported they would buy from online pharmacies claiming to be based outside the United

States. While this small and limited sample cannot possibly be taken to be representative of

all Americans, it does prove that there is indeed a sizeable market for online pharmacies. [49]

In a study conducted in Ireland by Lloyds Online Doctor with 1000 Irish adults, 73% of the

sample group were in favour of legislative changes to permit the online purchase of

medicines. [50] It is important to note the legality of buying prescription medicines online in

one’s country of residence does not influence the purchasing decisions of some consumers

nor the willingness-to-sell of some online pharmacies.

However, not all online pharmacies are legitimate. The internet has also proven to be the

ideal market and retail channel for counterfeiters. The internet offers a simple, cheap,

potentially discreet and convenient way for counterfeiters to market their wares around the

world to both the end-users of drugs and those intending to resell. The anonymity possible

by operating online allows counterfeiters to both hide their true identity and deceive

19

purchasers by synthesising the appearance of a legitimate pharmacy selling authentic

medicinal products. Counterfeiters may employ search engine optimisation (SEO) to

increase the ranking of their websites in search results and may also purchase keywords

relating to the drug or its trademarked name to include their site as a sponsored search

result to deceive and divert purchasers seeking the genuine product. [51] Due to the global

accessibility of websites and often-uncertain geographical location of the operators of

illegitimate online pharmacies, it is unclear if a single state or body should take responsibility

for investigating and shutting down these operations. International collaborations between

law enforcement agencies have successfully managed to investigate and shut down

illegitimate online pharmacies and other counterfeit operations around the world. INTERPOL

coordinates an annual week of action targeting online sales of counterfeit medicines known

as “Operation Pangea”. Starting first in 2008 with ten countries, the most recent Operation

Pangea VII conducted in 2014 involved the participation of DRAs, customs, national law

enforcement agencies and a number of private corporations from 113 countries. This

resulted in the seizure of nearly 10 million articles of counterfeit medicines worth $32 million,

434 arrests and nearly 12,000 websites shut down. [52] The scale of the issue is such that

concerted collaborative efforts such as these are likely to be more effective at combatting the

sale of counterfeit medicines over the internet than efforts by any one particular body.

Notwithstanding the fact that seizures of stock, arrests of operators and the shutting down of

illicit online pharmacies physically stymies the available supply of counterfeit medicines over

the internet; it is equally important and perhaps more effective as a permanent measure to

increase awareness amongst consumers of the dangers of counterfeit medicines and illegal

online pharmacies. Ideally, this will eliminate the lucrative market that ensures counterfeiters

and their distributors persist online.

Illegitimate online pharmacies are associated with the sale of counterfeit medicines and the

use of deceptive practices. [56] To explore further what measures can be taken to reduce the

prominence of these illegal pharmacies and educate consumers on their identification, it may

perhaps be best to illustrate what consumers encounter should they try to purchase

medicines online. A Google® search using the following search terms: “buy amoxicillin

online” returned approximately 1.56 million results of which the top four are exhibited in

Figure 22. According to a number of studies, the top 4-5 results of an online search receive

the vast majority (60-70%) of click-through traffic. [53]

20

The fourth result listed in Figure 2 led to a website advertising itself as a legitimate online

pharmacy operating in Cyprus. However, their contact email address uses a Chinese-

registered (.cn) domain. The pharmacy claims to require prescriptions to be emailed or faxed

after ordering yet also offers “trial packs” of three different erectile dysfunction medications

which constitutes highly unsafe practice and suggests that fulfilling the aforementioned

prescription requirement is not a prerequisite for buying medicines.

Three of the top four results do not lead to the URL listed in the search result which include

the domain names of legitimate (but unrelated) local businesses registered with an Irish (.ie)

top-level domain. It is likely that the websites of many other local businesses from around

the world have been hijacked in a similar manner so that users from around the world

searching for their keywords will be presented with apparently local search results. This

deceptive technique gives users the illusion that the site they are entering is legitimate and

based in their home country. Two of these results redirected to the domain

“ultrapills24.com” and one result redirected to the domain “drugs24h.net” yet both sites were

of identical design and content. Obtaining the registration details for each domain using the

WHOIS protocol revealed that both domains were registered within the past 12 months using

bogus contact details. [54] Using the same search engine to identify identical sites based on

design and phone contact details provided returned 354 results with a mixture of “generic”

domain names and domain names such as “cvs-online-pharmacy.com” which are chosen to

be similar to legitimate businesses with an intention to deceive consumers. All of these

online pharmacies were similar in that their site branding was generic, prices were unusually

low and all heavily promoted lifestyle drugs such as those used for sexual enhancement. All

of these identical sites advertised that they did not require a prescription. While it is not

certain that these pharmacies are selling counterfeit medicines, their deceptive marketing

and the absence of genuine contact details is indicative of an illegitimate operation. The

above is only one small sample of the deceptive practices that consumers may encounter

online. A large meta-analysis including 76 studies with original data found that the quality

and characteristics of online pharmacies varied enormously and concluded that minimisation

of the risks involved with using online pharmacies can be achieved through a combination of

international legal policy change and enforcement as well as increasing the health literacy of

consumers and empowering them to employ their critical faculties to safely buy medicines

online. [55] Search engine operators should take appropriate steps to modify their algorithms

Figure 2

21

to flag hijacked and/or otherwise potentially illegitimate websites so as to reduce their

ranking in search results in lieu of legitimate online pharmacies.

The findings of a notable report published by European Alliance for Access to Safe

Medicines known as “The Counterfeiting Superhighway” were reported in a number of major

mainstream media outlets. In this report, it was found that 62% of the products received in

the study were counterfeit or otherwise substandard and that a sizeable number of online

pharmacies were operating both dangerously and illegally. [56]

Consumers must be educated as to how to identify these illegitimate operations and the

risks involved in dealing with them. In addition, making a verifiable mark to certify legitimate

online pharmacies and increasing public awareness of this mark may also be highly

beneficial. With Directive 2011/62/EU, the European Commission introduced a “common

logo” to be prominently visible and universally identifiable on each page of the websites of

legal online pharmacies operating within the EU. Its implementation is scheduled to be

complete by mid-2015. [57] In the UK, the General Pharmaceutical Council operates a

national logo for legitimate online pharmacies operating in Britain. Each logo carries the

unique registration number of the pharmacy and is hyperlinked to the pharmacy’s entry on

the national register of pharmacies. As it is however quite trivial for a determined seller of

counterfeits to falsify this logo and indeed the website to which it links, the General

Pharmaceutical Council recommends that consumers independently confirm the legality of

the pharmacy by checking the registration status of the named pharmacist, pharmacy

premises and to avoid pharmacies which do not require a prescription or ask questions on

one’s health. [58]

International collaboration: Essential but difficult

In 2006, the WHO launched the International Medical Products Anti-Counterfeiting Taskforce

(IMPACT) in response to the growing issue of pharmaceutical counterfeiting. It executes its

functions through the activities of five working groups, namely; the legislation, regulatory

implementation, enforcement, communication and technology groups. Legislation must be

updated around the world to reflect the seriousness of the crime. So long as pharmaceutical

counterfeiting does not face the same investigation and same penalties as other organised

crime, there is little deterrent for large, sophisticated counterfeiting operations. [59] IMPACT’s

enforcement working group in conjunction with Interpol have trained law enforcement

officers and have carried out a number of joint operations against counterfeiters in Africa and

Asia. The communications working group focuses on both disseminating education to

relevant stakeholders ranging from patients to those involved in the supply and on promoting

the policy changes proposed by IMPACT. This has in the past lead to some changes such

as the further development of the WHO’s rapid alert system which is used to alert global

audiences to the presence of counterfeits on the market. [46] International collaboration is not

without some barriers however and competing economies may often stand in the way of

tackling domestic counterfeiting and collaborative efforts to tackle same on a global scale for

the benefit of their own economy. An example of this can be seen in China’s weak

enforcement in response to Chinese counterfeits being branded as “Made in India”. Some

authors have perceived this to be a strategic move to undermine the Indian pharmaceutical

industry with which China competes heavily. [60] It is important that diplomacy is used to

reach an international understanding of the collective responsibility of all countries to ensure

pharmaceutical counterfeiting faces robust opposition

22

Conclusion

Counterfeit medicines pose a number of problems for many stakeholders in healthcare and I

believe that it is incontrovertible that a concerted global response by all these stakeholders

will be required to achieve a truly satisfactory solution to the problem. While developed

countries with powerful and established drug regulatory authorities such as Ireland rarely

experience significant problems, regions where counterfeiting is endemic suffer hugely both

in terms of their public health and economy. Counterfeit medicines have been shown to

cause harm leading up to death, render authentic drugs ineffective through resistance and

tarnish the reputation and public trust for allopathic medicine and the many stakeholders

involved in its delivery from pharmaceutical industry to healthcare practitioners.

The barriers to international collaboration must be removed through diplomacy and

advocacy for working towards the common good of mankind as opposed to the individual

good of certain economies and regions. The counterfeiting of pharmaceuticals harms

generation after generation and to my mind, constitutes one of the most odious and morally

repugnant crimes. It is in humanity's collective interest and it is indeed humanity's collective

responsibility to eliminate counterfeiting of medicines.

The problems caused by counterfeit medicines may be addressed in a number of ways. The

complexity of global pharmaceutical trade and the distribution channels which supply

users/suppliers of medicines from manufacturers located around the world make distribution

complex and prone to weaknesses and errors. Considering that governments and their

regulatory bodies must support drug manufacturers (who are also victims of counterfeiters), I

would think that effective and enforceable legislation with regulatory oversight is crucial to

ensure that legitimate supply chains are managed to a high standard and are difficult to

compromise by counterfeiters. The use of technology in tracking and tracing products

throughout the supply chain has shown a great deal of promise with competing technologies

such as RFID and 2D barcoding. Many other security technologies which may be applied to

products or packaging also prove a highly useful component of an anti-counterfeiting

strategy as they may deter counterfeiters, assure consumers and provide conclusive

evidence of counterfeiting to assist in securing convictions for criminal cases of

counterfeiting. Though many of these technologies are sophisticated and expensive,

innovative systems such as mPedigree that require only cheap and ubiquitous technologies

have proven to be highly effective in developing countries where counterfeiting is an

endemic issue.

The rising popularity of buying medicines online has brought about a number of challenges,

not least of which are the many concerns raised over the quality of these pharmacies’

products which may often be of substandard quality or indeed counterfeit. While convenient

for patients, the internet is also an ideal market for counterfeiters as the anonymity it affords

eases deception, decreases risk and opens access to a global market with potentially large

spending power.

The problems posed by counterfeits are numerous and the conditions which allow for

counterfeiting are complex involving a great number of factors and parties. The economic

disadvantages facing the developing world has fuelled demand for counterfeit products and

the increasing experience and technological capacity of counterfeiters has increased

availability of these potentially life-threatening goodse around the world.

23

To address the problems caused by counterfeit medicines, it is necessary to reduce the

number of counterfeit medicines reaching patients. Reducing supply of counterfeit medicines

is a complex task and will necessarily require a concerted, international effort involving all

parties with involvement in production, supply and regulation of medicinal products. In the

interim, rather than eliminating supply, it is likely to be less technically challenging and

perhaps more effective to starve counterfeiters of their market. It is imperative that the public

is fully aware of the risks and consequences of counterfeit medicines and that they are

educated as to how best to identify counterfeit products. It is important first to reduce

demand for counterfeit medicines prior to reducing supply.

24

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