Chapter 8

EU Falsified Medicines Directive:

Requirements and Implications for
Multi-Stakeholder Healthcare Delivery
By James A. Smith, B. Naughton, A. Kramm, Graham Smith, A. Ohanjanyan, Mark De Simone, Rob Horne and
David A. Brindley

Objectives amending Directive 2001/83/EC on the

Community code relating to medicinal products
qq Introduce the problem of falsified medicines
for human use, as regards the prevention of
the entry into the legal supply chain of falsified
qq Define falsified and counterfeit medicines
medicinal products
qq Define active substances and excipients
qq Commission Implementing Regulation (EU) No
699/2014 of 24 June 2014 on the design of
qq Explain the aims and scope of the Falsified
the common logo to identify persons offering
Medicines Directive (FMD) Directive
medicinal products for sale at a distance to
2011/62/EU)
the public and the technical, electronic and
cryptographic requirements for verification of
qq Identify requirements for different stakeholders
its authenticity
in the medicines supply chain arising from
the FMD
qq Commission Delegated Regulation (EU) No
1252/2014 of 28 May 2014 supplementing
qq Discuss challenges in implementing FMD
Directive 2001/83/EC of the European
requirements
Parliament and of the Council with regard
to principles and guidelines of good
qq Identify relevant existing EU initiatives
manufacturing practice for active substances
for medicinal products for human use
qq Provide a list of third countries

qq Outline expected timelines for implementation Introduction

of the FMD Falsified medicines, as defined by the European Medicines
Agency (EMA), are fake medicines that pass themselves
qq Evaluate potential developments in detecting off as real, authorised medicines. Such medicines pose a
and managing falsified diagnostics significant public health risk as they may lack active ingre-
dients, contain dangerous contents, contain incorrect doses,
or be inappropriately labelled.1 According to the World
DIRECTIVES, Regulations and Health Organisation (WHO), Spurious/Falsely-Labelled/
Guidelines Covered in this Chapter Falsified/Counterfeit (SFFC) medicines comprise up to
1% of market value in the developed world, with the global
qq Directive 2011/62/EU of the European figure rising to 10%2,3 of a pharmaceuticals market worth,
Parliament and of the Council of 8June 2011 more than $300 billion (US) per year.4 Remarkably, efforts

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Chapter 8

Figure 8-1. Comparison of EU FMD and Other Countries Falsified Medicines Legislation

EU USA/Worldwide

1998 - An EU Green Paper on Counterfeiting in the

Single Market studies the pharma industry

2000 - In Italy, the Bollini Law requires drugs to be

tracked to the point of sale using two bar codes
1998 - Prescription Drug Marketing Act provides a
legal basis for combating fake medicines
2005 - New laws in Greece and Belgium compel 1980s
drug manufacturers to adopt mass serialisation
2004 - FDAs Counterfeit Drug Taskforce sets a
1990s framework for rollout of an ePedigree scheme by
2006 - European Commission warns about fake 2007
drugs on the Internet and issues resolution on 2000
Counterfeit medicines
2005 - Despite assurances, market players make
2001 slow progress toward deploying tracking technology
2007 - Industry associations such as EFPIA look
for standardisation and the adoption of second
technology 2002
2006 - Pfizer works on a proprietary mass
serialisation system, while EPC looks for an industry
2008 - European Commission launches a public 2003 standard
consultation on anti-counterfeiting measures
2004 2006 - WHO launches the International Medical
Products Anti-Counterfeiting Taskforce (IMPACT)
2008 - Responses to the public consultation are 2005
made public

2006 2007 - FDA declares itself disappointed with

ePedigree progress and targets adoption by 2010
2008 - Adoption of the proposal for the Commission
for a Directive of the European Parliament and of 2007
the Council amending Directive 2001/83/EC
2008 - California publishes E-Pedigree
Requirements, which are scheduled to go into
2008
effect in a phased approach between 201517
2011 - Directive 2011/62/EU introduces EU-wide
rules for the importation of active substances 2009
2011 - California also extends the deadline for roll-
out of its state level scheme from 2007 to 2011
2011 - Commission Implementing Decision of 2010
23 January 2013 on the assessment of a third
countrys regulatory framework
2011 2008 - FDA looks at technologies for the ID,
validation, track and trace and authentication of
prescription drugs
2012
2013 - New EU legislation becomes applicable

2013 2012 - Switzerland, Israel, Australia, Singapore,

Brazil and Japan are adopted as third countries
2014 - Good Manufacturing and Distribution
2014
Practices (GMP and GDP) are to be adopted
2013 - US and New Zealand are adopted as third
countries
2014 - Common logo design for legally-operating
online-websites is implemented

2014 - Safety features: unique serial number

specifications and verification system are
implemented

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 EU Falsified Medicines Directive: Requirements and Implications for Multi-Stakeholder Healthcare Delivery

Table 8-1. Definitions of Key Terms in This Chapter

Term Definition Source

Spurious/Falsely- Medicines deliberately and fraudulently mislabelled with respect to World Health
Labelled/Falsified/ identity and/or source. Organisation1
Counterfeit (SFFC)
Medicines
Falsified Medicine Any medicinal product with a false representation of: (a) its identity, Falsified Medicines
including its packaging and labelling, its name or its composition Directive2
regarding any of the ingredients, including excipients and strength
of those ingredients; (b) its source, including its manufacturer,
its country of manufacturing, its country of origin or its marketing
authorisation holder; or (c) its history, including records and
documents relating to distribution channels used.
Counterfeit Medicine Any medicinal product that does not comply with intellectual property European
rights and/or infringes on trademark law. Medicines Agency3

1. WHO, Medicines spurious/falsely-labelled/fasified/counterfeit (SFFC) medicines (http://www.who.int/mediacentre/factsheets/fs275/en/)

2. Directive 2011/62/EU of the European Parliament and Council amending Directive 2001/83/EC on Community code relating to medicinal products for
human use, as regards the prevention of the entry into the legal supply chain of falsified medicinal products (http://eur-lex.europa.eu/LexUriServ/LexUriServ.
do?uri=OJ:L:2011:174:0074:0087:EN:PDF).
3. European Medicines Agency, Falsified Medicines Webpage (http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000186.jsp).

to estimate the global market value for fake medicines are its country of manufacturing, its country of origin or
as high as $75 billion (US).5 its marketing authorisation holder; or (c) its history,
Pioneering attempts to address this important global including the records and documents relating to the
health issue, the European Parliament and Council of the distribution channels used.
European Union adopted the Falsified Medicines Directive
(FMD), Directive 2011/62/EU6 and delegated acts and Note: the definition does not include unintentional quality
regulations.7,8 Adoption of the FMD has been described defects and is without prejudice to infringements of intellec-
as the single largest change in the pharmaceutical industry tual property rights. Confusingly, although the two terms
in the last 40 years,9 and resulted from recognition of the clearly are distinct, SFFC medicines often are referred to
issues significance10 (Figure 8-1). This chapter provides a collectively as counterfeits, and those producing falsified
comprehensive overview of this significant policy, outlines medicines may be termed counterfeiters (e.g., WHO).13,14
anticipated requirements and means of execution, and dis- Greater nomenclature clarity and consistency would
cusses implications for multiple stakeholders involved in be useful. Within WHO Member States, there is little
healthcare delivery. consensus in defining counterfeit and falsified drugs, 15
creating considerable difficulty in global discussions. The
Defining Falsified Medicines EU has attempted to standardise the terminology, and the
Understanding the meaning of falsified medicines is authors recommend the definitions used herein (Table 8-1)
critical to understanding the FMDs scope. The terms be adopted worldwide to facilitate standardisation in both
counterfeit and falsified medicine often are confused discussion and policy.
and applied incorrectly; counterfeit medicines do not
comply with intellectual-property rights or infringe trade- Problem Scope
mark law, whereas falsified medicines are fake medicines SFFC medicines are not a new concept; however, the advent
designed to mimic real medicines.11 This difference and the of the Internet and e-pharmacies has augmented their
need for explicit definitions is emphasised by the European threat. SFFC medicines appearance in international com-
Medicines Agency (EMA).12 The FMD defines falsified merce was mentioned first in 1985 at the WHO Conference
medicinal products as: of Experts on Rational Drug Use in Nairobi, Kenya.16,17
Any medicinal product with a false representation of: Increasing international trade and the increase in online
(a) its identity, including its packaging and labelling, pharmaceutical sales has facilitated entry of SFFC medi-
its name or its composition as regards any of the ingre- cines into the complex supply chain,18 eventually leading
dients including excipients and the strength of those WHO to establish the International Medical Products Anti-
ingredients; (b) its source, including its manufacturer, Counterfeiting Taskforce (IMPACT) in 2006.19 More than

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Chapter 8

Figure 8-2. Routes in the Medicinal Product Supply Chain by Which Falsified Active Substances may Reach Patients

Pharmaceutical Ingredient

Legitimate pharmaceutical Illegitimate manufacturers

Wholesalers Illegal suppliers Illegal online sales

Legal online Key:

Hospitals Retail pharmacies
pharmacies
Legal route
Illegal route

PATIENTS

50% of medicines purchased online from illegal sites, which substances (sometimes also called active pharmaceutical
do not reveal their physical addresses, have been found to ingredients (APIs)) sourced from non-EU countries and
be SFFC medicines.20 However, SFFC medicines also may the point at which patients receive medication from a phar-
reach patients via the legal supply chain (Figure 8-2).21 macist or delivery via the internet.
SFFC medicines often are perceived as a problem Similar to other recently introduced legislation in
largely affecting less economically developed countries and the EU, such as ATMP Regulation (Regulation (EC) No
high-cost drugs (e.g., the 1985 WHO Conference Report 1394/2007), one of the FMDs central aims is harmonisation
suggested only high-cost drugs were affected). However, of falsified medicines regulation across the EU. Delegated
the problem actually affects high- and low-cost products, acts ensure each Member State implements them uniformly,
including branded and generic drugs in more- and less- ensuring consistency throughout the EU. The directive also
economically developed countries (Table 8-2). For example, emphasises falsified medicines are a global problem, and in
falsified vials of the relatively high-cost breast cancer drug the interests of global health, cooperation with international
Herceptin were confirmed in Germany and suspected in bodies is essential with regard to falsified medicines.
Finland, Austria and Sweden, following their theft in Italy.
In France in 2013, 1.2 million doses of the common drug Requirements
aspirin were seized.
The FMD introduces new requirements for various stake-
To attempt to address the problem of falsified medi-
holders in medical supply chains, who can be categorised
cines, the EU adopted the FMD in 2011.
broadly as manufacturers, brokers, wholesalers and retailers.
These requirements are outlined in Table 8-3. Introducing
Falsified Medicines Directive safety featuresmandatory tamper-evident seals and
Aims and Scope unique pack identificationon packaging will provide
The FMD amended Directive 2001/83/EC on the assurance of medicines authenticity. The FMD substan-
Community code related to medicinal products for human tially changes the European framework for the supply of
use22 and aims to tighten medicinal product distribution medicines, and also will include businesses traditionally not
chain control and protect consumers from falsified medi- regulated directly: medicinal product brokers, who do not
cines. FMD addresses problems arising from the medicines handle products physically. Further, it provides definitions
supply chains increasing complexity, with the Internet being for active substances and excipients (Table 8-4), and intro-
one of the biggest threats. Controls and checks throughout duces Good Manufacturing Practice (GMP) guidelines for
the supply chain are to be strengthened, including active active substances.

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 EU Falsified Medicines Directive: Requirements and Implications for Multi-Stakeholder Healthcare Delivery

Table 8-2. Worldwide Examples of SFFC Medicines From 2008 to Present1,2

SFFC Medicine Country/Year Report

Herceptin (for breast cancer) Finland, Germany, Vials initially labelled Herceptin thought to have labels and packaging
Austria, Sweden, 2014 tampered with, following theft of vials in Italy. Product not identified at
hospital level, but suspected in wholesalers in several countries.3
Omeprazole (for Germany, 2013 Fake drugs supplied to wholesale drug distributors and reached
gastroesophageal reflux patients.4
disease)
Aspirin (multiple clinical France, 2013 1.2 million doses of fake aspirin seized. Largely consisting of glucose
indications) and containing no active ingredient.19
Avastin (for cancer treatment) US, 2012 Affected 19 medical practices in the US. Drug lacked active ingredient.
Viagra and Cialis (for erectile UK, 2012 Smuggled into the UK. Contained undeclared active ingredients with
dysfunction) possible serious health risks to the consumer.
Truvada and Viread (for HIV/ UK, 2011 Seized before reaching patients. Diverted authentic product in falsified
AIDS) packaging.
Zidolam-N (for HIV/AIDS) Kenya, 2011 Nearly 3000 patients affected by falsified batch of their antiretroviral
therapy.
Alli (weight-loss medicines) US, 2010 Smuggled into the US. Contained undeclared active ingredients with
possible serious health risks to the consumer.
Glibenclamide (anti diabetic China, 2009 Contained six times the normal dose. Two people died, nine people
medicine) were hospitalized.
Seretide Evohaler (asthma) UK, 2009 Batch recalled after information from EU customs office indicated
product was falsified.
Metakelfin (antimalarial) United Republic of Discovered in 40 pharmacies. Drug lacked sufficient active ingredient.
Tanzania, 2009
Enbrel (rheumatoid arthritis) UK, 2008 Diverted authentic product in falsified packaging was seized before
reaching patients.

1. WHO, Medicines: spurious/falsely-labelled/ falsified/counterfeit (SFFC) medicines (http://www.who.int/mediacentre/factsheets/fs275/en/)

2. Royal Pharmaceutical Society Policy Statement: Falsified Medicines Directive (http://www.rpharms.com/promoting-pharmacy-pdfs/falsified-medicines-
sept-2013.pdf ).
3. European Medicines Agency alerts EU healthcare professionals after vials of falsified Herceptin identified (http://www.ema.europa.eu/docs/en_GB/docu-
ment_library/Press_release/2014/04/WC500165501.pdf ).
4. Jack A. Teva Discovers Sophisticated Fakes of Popular Drug. Financial Times (http://www.ft.com/cms/s/0/bd988804-afed-11e2-8d07-00144feabdc0.
html#axzz3Ys9GLBhw).

Not all medicines will be subject to the FMDs rules. product packaging to: verify whether the packaging has
The directive states prescription medicines must bear the been tampered with (tamper-evidence), and verify the
safety features mentioned above, whereas those not subject products authenticity and identify an individual product
to prescription shall be exempt from the requirements. pack (unique identifier). In a concept paper released for
There are exceptions: if risk assessment excludes them, public consultation in 2011,23 the European Commission
prescription medicines will not require safety features and, outlined expected requirements for these features. For tam-
conversely, nonprescription medicines deemed particularly per-evidence, the technical specification choice is left to the
vulnerable to falsification will require the features. Risk manufacturer and specific guidance is not given. However,
assessment to determine exceptions should include consid- for the unique identifier, specific technical guidance is pro-
erations of price, sales volume, previous cases of falsification vided: the only way to uniquely identify a pack is to label
in the EU or third countries, implications of falsification for it with a randomised serialisation number affixed to the
public health and severity of the condition to be treated. package by a carrier holding the number. This carrier most
Any excepted medicines must be listed in a delegated act. likely will be a 2-D barcode, although radio-frequency iden-
tification also has been proposed. The serialisation number
Directive Implementation then is checked against its entry in the repositories system,
which verifies its authenticity.
Perhaps the most significant regulation imposed in the FMD
For this system to be successful, a reliable verification
is the requirement for new safety features for medicinal
system must be in place. Since randomised numbers could

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Table 8-3. Different Medicinal Product Supply Chain Stakeholder Requirements Under the FMD

Stakeholder Requirements/Relevant Legislation

Multiple Packagers, repackagers, wholesale distributors, pharmacies/retailers and possibly others must be able to
verify the medicinal products authenticity, uniquely identify individual packs and maintain a repository system
in which to store identification data. They must be able to determine whether the outer packaging has been
tampered with.
Active substance importers, manufacturers and distributors established in the EU must register their activity
with the Competent Authority of the Member State in which they are established.
Each Member State must ensure the import of active substances from outside the EU, intended for use
in the manufacture of a medicinal product, is accompanied by a written confirmation from the Competent
Authority of the non-EU country stating standards of manufacture at the active substance manufacturing site
are equivalent to EU requirements.
The Competent Authority of the Member State shall ensure legal requirements for manufacturers are met by
inspection of facilities, which may be unannounced. Manufacturers and wholesale distributors are subject to
repeated inspections.
Manufacturer Any actor in the supply chain that packages medicinal products must hold a manufacturing authorisation.
Manufacturing authorisation holders who are not the original manufacturers must only remove, replace or
cover the original safety features under strict conditions; if the product is repackaged, safety features must
be replaced by equivalent safety features.
Manufacturers must inform the Competent Authority and marketing authorisation holder immediately
should the manufacturer obtain information that medicinal products (manufactured under the scope of the
manufacturing authorisation) may be falsified, regardless of whether those products are being distributed
through the legitimate supply chain or by illegal means.
Active substance manufacturers should be subject to inspections on the basis of risk-analysis, as well as on
the grounds of suspected noncompliance.
Regardless of whether an active substance is manufactured inside or outside the EU, its manufacture should
be subject to Good Manufacturing Practice. A legally binding act regarding GMP for active substances has
been introduced.
Broker Introduction of the brokering concept for finished medicinal products and provision of a new definition for
brokering: All activities in relation to the sale or purchase of medicinal products, except for wholesale
distribution, including physical handling and consisting of negotiating independently and on behalf of another
legal or natural person.
Brokers must register with the Competent Authority of the EEA Member State in which they are established.
Wholesaler Wholesale distributors should verify their supplying wholesale distributors are holders of a wholesale
Distributors distribution authorisation.
A person exporting medicinal products from the EU, including those with the sole purpose of exporting
medicinal products, are considered wholesale distributors and are, as such, subject to relevant provisions
and Good Distribution Practices.
A list of wholesale distributors complying with EU regulations based on inspection by a Competent Authority in
a Member State will be published in a database established at the EU level.
Retailers (Suppliers Companies selling medicines online to members of the public must be authorised and require a common
to the Public) logo to be displayed on their websites (Figure 8-3), which should be linked to the website of the Competent
Authority for the country in which the retailer is established. Websites of all Member States and of the
EMA should explain use of the logo, and all of those websites should be linked to provide comprehensive
information to the public.
Member States are allowed discretion regarding conditions for the supply of medicines to the public on their
territory.
Given risks of online retail, Member States may, in principle, restrict sale of medicinal products to
pharmacists alone. However, these restrictions should not unduly restrict functioning of the internal market.
A list of compliant retailers selling medicinal products at a distance should be provided to the public by each
Member State.
Community Pharmacies will be required to authenticate medicines at the point of dispensing with an approved FMD-
Pharmacies compliant authentication service to ensure medicines supplied are from legitimate sources with clear
(Independent and distribution histories.
Multiple) In keeping with their role in the community as the medicines experts, they also will be responsible for
providing patient advice concerning queries relating to falsified and counterfeit medicines.
Hospital Hospital dispensaries may be given special dispensations in certain circumstances with regard to FMD
Dispensaries/ compliance, but it generally is understood they, too, will be expected to comply with the majority of FMD
Pharmacies requirements.
Hospital pharmacies may encounter problems with authentication of medicines issued within the hospital
and returned to stock as some medication packs are used for multiple patients and, therefore, multiple pack
authentications, which is a problem not experienced by community pharmacies.

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 EU Falsified Medicines Directive: Requirements and Implications for Multi-Stakeholder Healthcare Delivery

Table 8-4. FMD Definitions of Active Substances and Excipients

Term Definition With EU FMD

Active Substance Any substance or mixture of substances intended to be used in the manufacture of a medicinal
product and when used in its production, becomes an active ingredient of the product intended to
exert a pharmacological, immunological or metabolic action with a view to restoring, correcting or
modifying physiological functions or to make a medical diagnosis.
Excipient Any constituent of a medicinal product other than the active substance and packaging material.

be reproduced easily, the serialisation number must be With this legislation, the EU aims to protect its Member
checked in to a repositories system and after its final use, States, but also supports recognising equivalent scientifi-
removed or checked out of the system (Figure 8-3). Such cally based standards worldwide, helping protect the public
a system would have various benefits, for example, allowing better and provide a greater level of protection on a wider
recall of medicines, safety messaging, notification of expired international scale.
or suspicious medicine and information on previously dis-
pensed medicine, all based on information stored in the GMP for Active Substances
serial number and/or verification system.
Commission delegated Regulation (EU) No 1252/2014
In addition to those covered in Table 8-3 and made
supplements Directive 2001/83/EC of the European
explicit in FMD, the introduction of unique product identi-
Parliament and the Council with regard to principles and
fiers may elicit new stakeholders in the medicinal product
guidelines of GMP for active substances for medicinal
supply chain: those who establish and maintain the verifi-
products for human use.27 Continuing with one of the
cation systems and repositories. Several organisations are
FMDs central aims, the regulation strives to promote use
beginning to address unique identifier requirements, and
of harmonised standards at a global level; therefore, devel-
some existed prior to FMDs publication (Table 8-5). Such
oping guidelines aligning with those established by the
organisations will need to comply with several requirements
International Conference on Harmonisation (ICH).
specified in the FMD; notably, safeguards protecting per-
Broadly summarising the regulation:
sonal and commercially sensitive information should be in
place and the FMD applies without prejudice to Directive
95/46/EC on protecting individuals with regard to process- Figure 8-3. An Example of the Common Logo Online
ing personal data and the free movement of such data.24 Retailers of Medicines Must Display

Third Countries
Under the FMD, countries outside the EU are obliged to
provide written confirmation active substances exported
from their country adhere to Good Manufacturing Practice
(GMP) standards equivalent to those in the EU. Third coun-
tries can be added to a white-list if the countrys regulatory
framework applicable to active substances exported to the
Union and the respective control and enforcement activi-
ties ensure a level of protection of public health equivalent
to the [EU].25 So far, Australia, Switzerland, Japan, the
US, Brazil and Israel have been added to the list, and other
countries are at various stages in the process (Table 8-6). In
particular, the assessment will take into account:
1. GMP rules in the country The flag corresponds to the Member State in which the retailer is registered.
2. regularity of GMP compliance inspections Only EU Member State national flags are allowed, as well as those of
3. effectiveness of GMP enforcement Norway, Iceland and Lichtenstein. By clicking on the image, the purchaser
4. regularity and rapidity of provision of informa- is directed to the entry of the retailer on the national list. Commission
implementing regulation (EU No 699/2014 details the requirements for
tion regarding noncompliant active substance the logo. (Image Source: http://ec.europa.eu/health/human-use/eu-logo/
production26 index_en.htm )

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Table 8-5. EU Initiatives Relevant to the FMD

European Stakeholder Model

European Stakeholder Model (ESM) is a partnership of organisations involved in the pharmaceutical supply chain, overseen by
a not-for-profit stakeholder organisation called the European Medicines Verification Organisation (EMVO). The ESMs aim is to
develop a safe, cost-effective and partnership-based pan-European medicines verification system using 2-D barcodes to address
FMD needs. ESM partners are establishing a coding and serialisation system to be implemented by Europes research-based
manufacturers, licensed parallel distribution companies, wholesalers and pharmacists. Their approach was tested at a national
level in Sweden.
eTACT: Anti-Counterfeiting Traceability Service for Medicines
eTACT is the European Directorate for the Quality of Medicines and Healthcare (EDQM) anti-counterfeiting traceability service for
medicines. The project has been developed in parallel to the FMD and is part of the Council of Europes global strategy to combat
SFFC medicines. eTACTs aim is to ensure traceability of individual packs of medicines using mass serialisation.
Similar to safety features introduced by the FMD (mandatory seals and unique pack identification), it is based on the principle
of generating a Unique Medicine Identifier (UMI) at the manufacturing stage. UMI allows traceability and verification by different
stakeholders in the legal supply chain. It is designed in accordance with the FMDs requirements and its future delegated acts
ASOP EU
Alliance for Safe Online Pharmacy (ASOP EU) comprises patient organisations, Internet intermediaries, healthcare providers,
pharmaceutical companies and supply chain stakeholders united in a campaign to make the Internet a safer place to obtain
medicines. It aims to become a trusted partner of the authorities in combatting the illegal sale of medicines online.

Personnel and equipment in the manufacturing Safety features introduced require substantial medicinal
areas vicinity must be sanitary. product packaging manufacturing process adaptations. As
To prevent cross-contamination when producing such, the FMD stated the timeline for implementing provi-
active substances harmful to human health, those sions relevant to safety features must be sufficiently long to
substances should be manufactured only in sepa- allow manufacturers to adapt their manufacturing processes
rate areas; for active substances with potential to be effectively. Some Member States already have authentication
harmful to human health due to potency, toxicity or or verification systems in place and will be given additional
infectiveness, risk assessment must be undertaken to time to adapt to the harmonised EU system. Several EU ini-
evaluate the potential need for separate production tiatives have emerged or exist already with relevance to various
areas. FMD components, including the unique identifier and, more
Detailed written records of production processes generally, combatting illegal drug sales via the Internet.
must be kept, and any changes affecting the active
substances quality should be communicated to Implications and Challenges
manufacturers using the active substance. Addressing falsified medicines ultimately requires global
Procedures must be in place allowing product recall cooperation. The FMD recognises the need for concerted
and investigation of concerns over active substance international effort against falsified medicines, in particu-
quality. lar regarding Internet sales. As such, Member States and
If the manufacture of any part of an active substance the European Commission are encouraging cooperation
is entrusted to another party, responsibilities of the and supporting ongoing international efforts on falsified
other party in terms of GMP quality compliance medicines. In line with this, and to promote the use of
must be clarified in writing. harmonised standards at a global level, delegated regulation
GMP must be applied to the repackaging and rela- regarding GMP for active substances31 adopted guidelines
beling process. in agreement with those established by ICH. If other
worldwide regulatory bodies act similarly and standardise
Timeline for Implementation terminology as suggested above, the battle against falsified
medicines will be greatly accelerated and facilitated.
The FMD was published in the Official Journal of the European
Despite these positive steps, many perceive FMD imple-
Union (OJ) 1 July 2011. This mandated all Member States to
mentation as a challenge. Costs for affected actors in the
transpose legislation into national law by the end of January
medical product supply chain likely will be considerable,
2013 with full compliance mandated within three years of
particularly regarding new safety feature requirements and
the publication of FMD delegated acts in the OJ.28 Delegated
accompanying systems; some have expressed concerns these
acts were expected in mid-2015; however, they have not yet
costs will make some medicines unaffordable and could
been published, and the delay between publication of the
impact parallel trade negatively, particularly given they often
FMD and the delegated acts been criticised.29,30
are repackaged.32 Complex information transfer required

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 EU Falsified Medicines Directive: Requirements and Implications for Multi-Stakeholder Healthcare Delivery

Figure 8-4. Flowchart Representing Product and Information Flow With Unique Product Identifiers and
Accompanying Verification and Repository Systems

Direct to Pharmacist Messaging

1. Recall
2. Safety messaging
3. Expired medicine
4. Suspicious medicine
5. M
 edicine dispensed previously

Patient Related Messages

1. Adherence support
Supply Chain Inputs 2. Patient information
Parallel Trader(s)
1. (Bio) Pharmaceutical Distributor(s) 3. E
 lectronic informed consent
(Re-packager)
Companies 4. Cross selling
2. Generic Manufacturing
Companies
3. Tools and Technology
Suppliers
4. Contract Manufacturing
Organisations Pharmacies
5. Parallel Trader Manufacturer(s) Wholesaler(s) 1. Hospital Patient(s)
(Re-packager) 2. Community/
retail
3. Independent
Serial Number 4. Dispensing
Verification clinicians
5. Internet

Potential Direct to
Unique serialization Authentication Patient Messaging (Using
of tamper resistant National Medicines and check-out of Pharmacist to sign up)
packaging with Serial Verification Repository Serial Number serial number after 1. Health community
random numbers Number Authentication dispensing to patients organisation
Upload 2. Community health provider
Check-in
3. Disease specific
foundations
4. Patient advocates
5. Payers
Key

Product transfer
Information transfer

for FMD compliance will necessitate substantial changes to Although other legislation aims to combat trade of falsi-
current system infrastructures, and ensuring these changes fied medicines worldwide (e.g., the Drug Quality and Security
are harmonised throughout the EU will be essential to suc- Act, H.R. 3204 in the US), with the FMD, the EU is leading
cessful implementation. an ambitious attempt to develop a harmonised approach to
This chapter has discussed implications for multiple tracking and labelling safe medicines and ensuring falsified
stakeholders in the medicinal product supply chain affected medicines do not reach patients by authentication at the dis-
by the FMD. However, ultimately, the most important stake- pensing point. The FMD applies directly to the EU; however,
holder affected by the directive is the patient, and issues with by promoting standardisation more broadly, patients through-
costs of implementation likely will be outweighed by patient out the world may benefit. While inevitably introducing costs
benefits. Beyond the clear benefits of reducing the prevalence and challenges to the medicinal product supply chain, this
of falsified medicines, there is considerable scope for wider historic regulation is an essential step toward a world free of
reaching impact. In particular, adoption of unique identi- falsified medicines, and should be perceived as such.
fiers and verification/repository systems could allow other Ultimately, the problem of falsified medicines is a major
health-related issues to be addressed: data generated could risk to patient safety, damaging public trust in healthcare
be used to measure and characterise patient behaviour with and the pharmaceutical industryreducing revenue avail-
regard to medicine, aid communication between pharmacy able to reinvest in R&D efforts to address unmet medical
and patient and allow development of tools to communicate needs. While investment in requisite manufacturing and
with and support patients directly (Figure 8-3). distribution infrastructure, particularly in primary and

Regulatory Affairs Professionals Society 79

Chapter 8

Figure 8-5. 21st Century Pharmacopeia

Therapeutics Devices

Small Molecules BIOLOGICS Medical Devices

(e.g., imatinib) Monoclonal Antibody (e.g., trastuzumab) (e.g., stents)

Cell Therapy Immuno Therapy Gene Therapy (e.g., Tissue Engineering

(e.g., MSCs) (e.g., chimeric alipogene tiparoved) (e.g., skin grafts)
antigen receptor-
modified T cells)

REGENERATIVE MEDICINE

COMBINATIONAL THERAPEUTICS

secondary care pharmacies, initially may be burdensome, small molecules (high volume, low cost) and mAb biolog-
generation of primary benefitsreduction in falsified ics (high cost, low(er) volume). However, a snapshot of
medicines and reimbursement fraud and tighter control contemporary basic science and clinical trial landscapes
of active pharmaceutical ingredientslikely will be swift. clearly indicates the future pharmacopeia is more complex,
Secondary benefits including reduced dispensing errors, moving away from allogeneic small molecules to complex
opportunity for patient engagement, providing informa- autologous therapeutics and combinational strategies, utilis-
tion about medicines and supporting optimal adherence, ing therapeutics and devices34 (Figure 8-5). Consequently,
electronic informed consent, real-time pharmacovigilance guidance and regulation pertaining to falsified medicines
and business intelligence are tractable and impactful. and devices must adapt.
Preventing falsified medicines and realising the FMDs
secondary benefits are not just legal requirements; they are Scope of Combination Therapies
healthcare professionals responsibilities at all stages of the
Combination therapies may be applied in a variety of
lifecycle33 to safeguard patient safety and improve patient
approaches, including a small molecule being co-admin-
outcomes.
istered with a biologic; for example, anti-TNFs and
Methotrexate. At the core of stratified and personalised
Potential Developments in Detection and medicine approaches is use of companion diagnostics to
Management of Falsified Medicines and identify patients with a disease-specific genetic marker,
Devices which indicates a high likelihood of efficacy arising from
The FMDs primary purpose is to identify and deter fal- application of a specific therapeutic. Finally, and more futur-
sified medicines in todays pharmacopeia, dominated by istically, combinational approaches include de-cellularised

Table 8-6. List and Status of Third Countries Requested to be Listed

Country Request Date Status, Publication Date in the Official Journal of the European Union (if adopted)
Switzerland 4 April 2012 Adopted, 22 November 2012
Israel 9 May 2012 Adopted 1 July 2015
Australia 18 September 2012 Adopted, 24 April 2013
Singapore 17 September 2012 No listing for the moment (relevant Singapore legislation provides for a non-
mandatory GMP certification scheme). Contacts ongoing. In the meantime, Singapore
issues written confirmation.
Brazil 4 October 2012 Adopted 1 July 2015
Japan 6 December 2012 Adopted, 4 June 2013
US 17 January 2013 Adopted, 11 June 2013
New Zealand 26 June 2013 Assessment on hold pending clarification of scope of existing MRA.
South Korea 22 January 2015 Equivalence assessment ongoing.

Source: http://ec.europa.eu/health/human-use/quality/index_en.htm

80 Regulatory Affairs Professionals Society

 EU Falsified Medicines Directive: Requirements and Implications for Multi-Stakeholder Healthcare Delivery

Table 8-7. Examples of Stratified Medicines and Companion Diagnostics

1. Meadows NA, Morrison A, Brindley DA, Schuh A, Barker RW. An Evaluation of Regulatory and Commercial Barriers to Stratified Medicine Development
and Adoption. Pharmacogenomics J. 2015 Feb;15(1):612.

xeno-derived and/or cadaveric scaffolds to which human 4. WHO, Pharmaceutical Industry (Internet) (cited 13 March 2015).
WHO website. http://www.who.int/trade/glossary/story073/en/.
cells are engrafted in tissue engineered approaches; and gene
Accessed 3 September 2015.
modified autologous immunotherapies. All permutations of 5. Beard S. Fake Pharmaceuticals are a $75 Billion Global Insutry
combinational therapies have major implications for effec- (Internet) (cited 17 March 2015). Marketplace World website.
tive implementation of the the FMD. http://www.marketplace.org/topics/world/fake-pharmaceuticals-are-
75-billion-global-industry. Accessed 3 September 2015.
6. Directive 2011/62/EU of the European Parliament and the Council
Companion Diagnostics amending Directive 2001/83/EC on the Community code relating
to medicinal products for human use, as regards the prevention o fthe
Companion diagnostics, applied with a (biological) thera- entry into the legal supply chain of falsified medicinal products. Off
peutic, are increasingly common feature of medical practice J Eur Union (Internet). 8 June 2011 (cited 29 April 2015). EUR-Lex
and biopharmaceutical company clinical trial pipelines. website. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:
Presently, only the therapeutic component of the treat- L:2011:174:0074:0087:EN:PDF. Accessed 3 September 2015.
7. Taaffe T. European Union has the Falsified Medicines Directive.
ment will be protected against SFFC by FMD-mandated BMJ 2012;345:e8356.
safety features. However, there is an incentive to falsify 8. Smith G, Smith JA, Brindley DA. The Falsified Medicines Directive:
the companion diagnosticwhich can command a high How to Secure Your Supply Chain. J Generic Med. In Press.
reimbursement level akin to some high-cost small mole- 9. Elvidge S. The Falsified Medicines DirectiveWhat Does It Really
Mean? Life Science Leader (Internet) (cited 13 March 2015). Life
culesboth to generate direct revenue from the counterfeit Science Leader website. http://www.lifescienceleader.com/doc/the-
diagnostic, but also potentially by generating a deliberate falsified-medicines-directive-what-does-it-really-mean-0001. Accessed
false positive to stimulate sales of legitimate and/or counter- 3 September 2015.
feit therapeutics. Therefore, while discussions pertaining to 10. Kovacs S, Hawes SE, Maley SN, Mosites E, Wong L and Stergachis
A. Technologies for Detecting Falsified and Substandard Drugs in
potential legislation to identify and control falsified devices Low- and Middle-Income Countries. PloS One. 2014;9(3):e90601.
are on-going among international regulators, positive syner- 11. European Medicines Agency. Falsified Medicines webpage (Internet).
gies between the FMD and the forthcoming EU Falsified EMA website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/
Device Directive (EU FDD) should not be overlooked, nor special_topics/general/general_content_000186.jsp. Accessed 3
September 2015.
should potential complexity in their parallel implementa- 12. Ibid.
tion and enforcement. 13. Op cit 2.
14. WHO, General Information on counterfeit medicines (Internet)
References (cited 13 March 2015). WHO website. http://www.who.int/medi-
1. Gostin LO, Buckley GJ, Kelley PW. Stemming the Global cines/services/counterfeit/overview/en/. Accessed 3 September 2015.
Trade in Falsified and Substandard Medicines. JAMA. April 24 15. Ibid.
2013;309(16);16934. 16. Ibid.
2. WHO, Medicines: spurious/falsely-labelled/falsified/counterfeit 17. WHO, The Rational Use of Drugs: Report of the Conference of
(SFFC) medicines (Internet) (cited 13 March 2015). WHO website. Experts, Nairobi, 2529 November 1985 (Internet) (cited 13 March
http://www.who.int/mediacentre/factsheets/fs275/en/. Accessed 3 2015) WHO website. http://www.who.int/medicines/services/coun-
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Pharm J (Internet) (cited 13 March 2015). The Pharmaceutical Journal 19. WHO International Medical Products Anti-Counterfeiting
website. http://www.pharmaceutical-journal.com/opinion/comment/ TaskforceIMPACT (Internet) (cited 13 March 2015). WHO
the-falsified-medicines-directive-time-to-get-it-right/20066783. website. http://www.who.int/impact/en/. Accessed 3 September 2015.
article. Accessed 3 September 2015. 20. Op cit 2.

Regulatory Affairs Professionals Society 81

Chapter 8

21. Op cit 6. 34. Brindley DA, Rakhi R, Fuerstenau-Sharp M, Kantoff P, Hollander

22. Directive 2001/83/ED of the European Parliament and of the Council G, Smith JA, et al. The Potential Application of Real-Time
on the Community code relating to medicine products for human use. Release Testing for the Biomanufature of Autologous Cell-Based
Off J Eur Union (Internet), 2001 (cited 13 March 2015). EC website. Immunotherpies. BioProcess Int. 2014;13(4(s));3443.
http://ec.europa.eu/health/files/eudralex/vol-1/dir_2001_83_cons/
dir2001_83_cons_20081230_en.pdf. Accessed 3 September 2015. Acknowledgments
23. European Commission, Delegated Act on the Detailed Rules for The authors wish to express their sincere thanks to the following organ-
Medicinal Products for Human Use, and its Verification: Concpet isations that have contributed to the CASMI Translational Stem Cell
Paper Submitted for Public Consultation (Internet), 2001 (cited 13 Consortium (CTSCC) as funding and events partners, without whom
March 2015). EC website. http://ec.europa.eu/health/files/coun- the consortium and the benefits it will bring to stem cell translation
terf_par_trade/safety_2011-11.pdf. Accessed 3 September 2015. would be constrained: GE Healthcare, CCRM, Sartorius Stedim Biotech
24. Directive 95/46/EC of the European Parliament and of the Council (formerly TAP Biosystems), Lonza, CIRM, SENS Research Foundation,
on the protection of individuals with regard to the processing of per- UK Cell Therapy Catapult, NIH Centre for Regenerative Medicine,
sonal data and on the free movement of such data (Internet), 1995 NYSCF, ThermoFisher Scientific, Eisai, Medipost (US), Medipost (Korea),
(cited 16 March 2015). EUR-Lex website. http://eur-lex.europa.eu/ Celgene, Roche and Oxford Biomedica. D.A.Brindley gratefully acknowl-
LexUriServ/LexUriServ.do?uri=CELEX:31995L0046:en:HTML. edges personal funding from the Oxford Musculoskeletal NIHR BRU, the
Accessed 3 September 2015. Said Foundation and the SENS Research Foundation. J.A. Smith gratefully
25. European Commission. Commission Implementing Decision: on acknowledges support from the CTSCC. The authors also acknowledge
the assessment of a third countrys regulatory framework applicable the invaluable support of Paul Thomas, Peter Fox, Adrian Hitchen and
to active substance of medicinal products for human use and of the Gavin Hanks at Aegate Ltd.
respective control and enforcement activities pursuant to Article
111b of Directive 2001/83/EC of the European Parliament and of
Disclosures
the Council. Off J Eur Union (23 January 2013).
This chapters represents the authors individual opinions and may not
26. Op cit 6.
necessarily represent the viewpoints of their employers. DA Brindley
27. Commission Delegated Regulation (EU) No 1252/2014 supple-
gratefully acknowledges support from the SENS Research Foundation
menting Directive 2001/83/EC of the European Parliament and
(Mountain View, CA). Brindley is a stockholder in Translation Ventures
of the Council with regard to the principles and guidelines of good
Ltd. (Charlbury, Oxfordshire, UK), providing cell therapy biomanufactur-
manufacturing practice for active substances for medicine products
ing, regulatory, and financial advice to clients in the cell therapy sector.
for human use. Off J Eur Union (Internet) 28 May 2014. EC website.
He is subject to the CFA Institutes codes, standards and guidelines and,
http://ec.europa.eu/health/files/eudralex/vol-1/reg_2014_1252/
as such, must stress this chapter is provided for academic interest only and
reg_2014_1252_en.pdf. Accessed 3 September 2015.
must not be construed in any way as an investment recommendation.
28. Op cit 3.
Additionally, at time of publication, Brindley and the organisations with
29. Taylor NP, European Regulatory Roundup: Commission Under
which he is affiliated, may or may not have agreed and/or pending funding
Fire for Delay in Implementing Falsified Medicines Legislation
commitments from the organisations named herein. B. Naughton and
(Internet) 2015 (cited 13 July 2015). RAPS website. http://
Brindley are consultants for Aegate Ltd. Naughton also is a registered UK
www.raps.org/Regulatory-Focus/News/2015/07/02/22832/
pharmacist and, therefore, complies with GPHC codes, standards and
European-Regulatory-Roundup-Commission-Under-Fire-for-Delay-
guidelines and stresses this publication is provided for academic interest
in-Implementing-Falsified-Medicines-Legislation-2-July-2015/.
only. Rob Horne has undertaken speaker engagements with honoraria from
Accessed 3 September 2015.
the following companies: Abbvie, Amgen, Biogen Idec, Gilead Sciences,
30. ODonnell P. EU Patients Will Wait Years for Counterfeit Med Fix
GlaxoSmithKline, Janssen, MSD, Pfizer, Roche and Shire Pharmaceuticals.
(Internet). Politico 2015 (cited 13 July 2015). Politico EU website.
He is founder and shareholder of a UCL-business, Spoonful of Sugar, pro-
http://www.politico.eu/article/eu-patients-will-wait-years-for-coun-
viding consultancy on medication-related behaviours to healthcare policy
terfeit-med-fix/. Accessed 3 September 2015.
makers, providers and industry. Graham Smith and Mark De Simone are
31. Op cit 27.
employees of Aegate Ltd.
32. Op cit 9.
33. Black N. The Cooksey review of UK health research funding. BMJ.
2006;333(7581):1231.

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