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1
Introduction
In the 1949 film The Third Man and the novel of the same name, Holly Martin learns that
his childhood friend Harry Lime has made a fortune diluting stolen penicillin and selling it on the
black market. In a dramatic confrontation on the Vienna Ferris wheel, Martin refers to Lime’s
earlier racketeering asking, “Couldn’t you have stuck to tires?” No, explains Lime, one of the
American Film Institute’s 100 greatest villains, “I’ve always been ambitious.” (AFI, 2003).
The theft, adulteration, careless manufacture, and fraudulent labeling of medicines1
continue to attract villains who, like Harry Lime, grow wealthy off their business. Although the
problem is most widespread in poor countries with weak regulatory oversight, it is no longer
confined to underground economies as in post-war Vienna. As of January 2013, gross
manufacturing negligence at a compounding pharmacy in Massachusetts had sickened 693
Americans and killed 45 (CDC, 2013). Less than a year earlier, 76 doctors in the United States
unknowingly treated cancer patients with a fake version of the drug Avastin (Weaver and
Whalen, 2012).
International trade and manufacturing systems obscure connections between the crime
and the criminal; in modern supply chains, medicines may change hands many times in many
countries before reaching a patient. To complicate the problem, medicines are mostly for sick
people. The effects of inactive, even toxic, drugs can go unnoticed or be mistaken for the natural
course of the underlying disease. This is most true in parts of the world with weak
pharmacovigilance systems, poor clinical record keeping, and high all-cause mortality, where
“friends or relatives of those who die are obviously saddened, but not necessarily shocked”
(Bate, 2010).
Deaths from fake drugs go largely uncounted, to say nothing of the excess morbidity and
time and money wasted by using them. The manufacture and trade in fake pharmaceuticals is
illegal and hence almost impossible to measure precisely. Even crude copies can blend in with
legitimate products in the market. The camouflage succeeds because drug quality is not
something consumers can accurately judge. This imbalance, also called information asymmetry,
makes the medicines trade vulnerable to market failure (Mackintosh et al., 2011). In short, “At
every step of the supply chain there is this unequal knowledge, and people are exploited because
of [it]” (Mackintosh et al., 2011, 2).
Market controls and oversight aim to correct the information imbalance in the medicines
market, but supervising sprawling multinational distribution chains is a “regulatory nightmare”
(The Economist, 2012). National drugs regulatory agencies (hereafter, regulatory agencies) are
responsible for assuring drug quality in their countries, a job that increasingly requires
cooperation with their counterpart agencies around the world (IOM, 2012). The World Health
Organization (WHO) has worked to facilitate this cooperation since 1985, but advancing the
public discourse on this topic has proven more difficult than anyone would have predicted then
(Clift, 2010).
1
The terms medicine, drug, and pharmaceutical are used interchangeably in this report in accordance with the
definitions listed in the American Heritage Stedman’s Medical Dictionary (American Heritage Stedman's Medical
Dictionary, 2012a, 2012b, 2012c).
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COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS
To start, different countries and international stakeholders cannot agree on how to define
the problem. When it is framed as one of counterfeit and legitimate drugs, many civil society
groups and emerging manufacturing nations see a thinly-veiled excuse to persecute generic drug
industries (Clift, 2010; The Economist, 2012). Large innovator pharmaceutical companies have
the most experience in finding and prosecuting pharmaceutical crime. This expertise brought
them a place in the WHO’s International Medical Products Anti-Counterfeiting Taskforce
(IMPACT), the largest international working group on drug safety to date. Involving these
companies with a WHO program, however, raised suspicions of civil society groups (TWN,
2010). Objections to the taskforce’s inception and confusion about its mandate from WHO
governing bodies further eroded support (TWN, 2010). WHO distanced itself from IMPACT
after 2010; the taskforce’s secretariat moved to the Italian drugs regulatory authority (Seear,
2012; Taylor, 2012).
IMPACT may no longer be active, but criminals and unscrupulous drug manufacturers
are. The Economist recently described the 21st century as “a golden age for bad drugs” (The
Economist, 2012). There is an urgent need for international public discourse on the problem. In
an effort to advance this discourse, the U.S. Food and Drug Administration (FDA) commissioned
the Institute of Medicine (IOM) to convene an a consensus committee on understanding the
global public health implications of falsified, substandard, and counterfeit pharmaceuticals. Box
1-1 presents the committee’s charge. (See Appendix B for committee member biographies.)
The committee met in March, May, July, and October of 2012 to hear speakers and
deliberate on its recommendations for this report. Small travel delegations of committee
members and staff also visited experts in Brasilia, Delhi, Geneva, Hyderabad, London, and São
Paulo in the summer of 2012. In total, the committee heard input of 106 experts in its
information gathering meetings. (See Appendix C for meeting agendas.) Additional literature
review informed the conclusions and recommendations presented in this report.
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INTRODUCTION
BOX 1-1
Statement of Task
The Institute of Medicine (IOM) is requested to convene an ad hoc consensus
committee of diverse experts to gather information and deliberate on approaches to
mitigating the global problem of substandard, falsified, and counterfeit pharmaceuticals and
products used in their manufacture. It will begin by developing among the committee
members and for this context consensus working definitions for the terms “substandard,”
“falsified,” and “counterfeit.” The committee will carefully distinguish between the
application of these terms to meet public health and legal needs. Then focusing specifically
on the public health aspects of the problem, the IOM committee will address the following
issues:
Trends: Using available literature, identify high-level, global trends in substandard,
falsified, and counterfeit (SFC) medicines including differences and similarities in
different global regions. Identify gaps in the evidence that complicate the analysis of
these trends. This is intended to provide context to the study, but not serve as an in-
depth analysis.
Risks in the supply chain: Identify the weaknesses in the supply chain that allow
falsified, substandard, and counterfeit drugs to circulate.
Health affects: Explain the public health consequences, to patients and at the
population level, of SFC drugs and how to measure this.
Standards: Identify areas where convergence of standards could contribute to
stronger regulatory actions.
Identification: Describe global regulatory processes, e.g. track and trace,
authentication, that distinguish genuine and high quality drugs from fake or
substandard drugs and identify what factors could be used for additional scrutiny of
the genuineness of the product.
Technology: Identify detection, sampling methods, and analytical techniques used
to identify counterfeit, falsified, and substandard drugs. Explain how these
technologies can be best used and implemented in a system to stop the circulation
of harmful drugs.
Collaboration: Assess effectiveness of regulatory approaches around the globe
including prevention, detection, track and trace systems, compliance, and
enforcement actions.
o Based on such an assessment, identify areas where collective action among
government regulatory authorities is most relevant and sustainable;
o Identify ways government, industry, and other stakeholders can work together to
strengthen supply chains and fight counterfeit, falsified, and substandard drugs;
o Identify areas where industry or other stakeholders are best equipped to act;
and
o Recommend a collaborative path forward. This includes recommending
definitions for the products in question that would be sensitive to the needs of
drug regulators around the world and focuses on the public health. It also
includes recommending how various regulators could collaborate on a global
and regional level to best address the problem.
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BACKGROUND AND TERMS
The committee’s first step in deliberating on the task in Box 1-1 was agreeing on
common terms to describe the products of interest. They reviewed the competing and often
overlapping definitions of the terms counterfeit, falsified, and substandard, as well as similarly
important concepts such as unregistered. As Tables 1-1 through 1-6 make clear, some of these
definitions have evolved over time with the trade and intellectual property debates of the last
twenty years coloring how people use words like counterfeit. The following brief background on
intellectual property, public health, and patent and trademark infringement gives some context to
this discussion.
Key Findings and Conclusions
A long and acrimonious history of applying intellectual property rights to medicines
colors the discussion about drug quality.
A counterfeit medicine is one that infringes on a registered trademark. The broad
use of the term counterfeit, meaning made with intention to deceive, is insufficiently
precise for formal, public discourse.
Substandard drugs fail to meet the specifications outlined by an accepted
pharmacopeia or the manufacturer’s dossier.
Falsified drugs are those that carry false representation of identity or source.
Unregistered drugs circulate without market authorization. Unregistered medicines
are suspect, though some may be of good quality.
Intellectual Property and Public Health
Intellectual property rights, particularly patent rights, allow the owner of a new product
or technology to recoup their research and development costs by charging prices far above the
marginal cost of production. Therefore, patent-protected medicines are expensive; the cost of
these drugs puts them out of reach of many patients. In developed countries, governments or
large private insurers can mitigate this problem (Rai, 2001). But in poor countries, health
insurance is limited and pricing far above marginal costs can exclude entire countries from the
medicines market (Yadav and Smith, 2012).
TRIPS and the Doha Declaration
The recent history of the international patent controversy began with the 1994 Agreement
on Trade Related Aspects of Intellectual Property Rights (TRIPS), which required signatories to
make patents available, either immediately or after a transition period (Barton, 2004; WTO,
1994) . However, a provision allowed governments to grant compulsory licenses, that is, to grant
a license to use a patent without the patent holder’s consent, subject to conditions laid down in
the agreement (WTO, 1994). Compulsory licenses are subject to prior negotiation with the patent
holder, but these negotiations too can be waived in cases of national emergency or extreme
urgency or for public non-commercial use (WTO, 1994).
As TRIPS entered into force antiretroviral drugs for HIV and AIDS were becoming
widely available in the in developed countries reducing AIDS-mortality dramatically within 4
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INTRODUCTION
years (CASCADE Collaboration, 2003; Osmond, 2003). The expense of the patent-protected
drugs put them out of reach for all but 2 percent of the approximately 2.5 million HIV and AIDS
patients in low- and middle-income countries (WHO, 2002). Tensions over patent protection
came to a head in 2001 when the Pharmaceutical Research and Manufacturing Association,
representing 39 major pharmaceutical companies, sued the South African government over a law
that allowed the manufacture of patent-protected AIDS drugs (BBC, 2001a; Simmons, 2001).
The association “bow[ed] to mounting public pressure” and dropped the case after disastrous
press (BBC, 2001b; Pollack, 2001; Swarns, 2001; The Economist, 2001). After 2001, innovator
drug companies began issuing more voluntary licenses at lower prices (Flynn, 2008).
Antiretrovirals would have still have been too expensive for the poorest patients if not for
Indian drug companies, exempted from TRIPS patent protections until 2005. In February 2001,
the Indian drug company Cipla offered its triple therapy combination of stavudine, nevirapine,
and lamivudine to Doctors Without Borders (an organization known by the French acronym
MSF) for less than $1 per patient per day, undercutting the cheapest voluntary license offer by
about 30 percent (McNeil, 2001; t'Hoen et al., 2011).
More recently, regulators and innovator pharmaceutical companies have devised other
ways to make patent protected drugs available in developing countries. The U.S. government
uses the FDA tentative approval process to guarantee drugs supplied through the Presidents
Emergency Program for AIDS Relief (FDA, 2013). Through this program, the FDA approves
both drug combinations (many not available in the United States because of patent controls) and
the producers in Asia and Africa that make the drugs at greatly reduced costs (FDA, 2013).
Drugs granted tentative approval “[meet] all safety, efficacy, and manufacturing quality
standards for marketing in the U.S., and, but for the legal market protection, … would be on the
U.S. market” (FDA, 2013).
Patent and Trademark Infringement
Patents, not trademark or trade dress, are the main source of tension between intellectual
property and public health. But both patent and trademark questions surfaced in 2008 and 2009
when European customs officials seized consignments of generic medicines in transit from India
to Latin American and sub-Saharan Africa (Brant and Malpani, 2011). The drugs were not under
patent in India, nor in the counties they were destined for, but a European Union (EU) regulation
allows customs officials, acting either on their own behalf or after a request from the rights
holder, to seize goods that may infringe on patents, trademarks, or copyrights (Ho, 2011; Miller
and Anand, 2009). Dutch courts interpreted this to mean that customs authorities are allowed to
treat in-transit goods as if they had been made in Holland (Ho, 2011). French and German
customs officials also seized drug shipments in the same period (Taylor, 2009).
Sometimes trademark misunderstandings delay consignments. In May 2009, German
authorities suspended a shipment of amoxicillin bound for Vanuatu in the Frankfurt airport on
the grounds that it might infringe on GlaxoSmithKline’s trademark name for the same drug,
Amoxil. When contacted, GlaxoSmithKline denied any suspicion of trademark infringement, by
which time the shipment was delayed four weeks (Mara, 2009; Singh, 2009).
Whether or not the use of national law to seize in-transit drug shipments is consistent
with international law, particularly the TRIPs agreement, remains an open question (Ho, 2011;
Ruse-Khan, 2011). Developing countries argue that such seizures violate TRIPs agreement
safeguards allowing the export of cheap generic drugs to countries unable to manufacture them
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COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS
(Ho, 2011). On the other hand, the Anti-Counterfeiting Trade Agreement, signed by Australia,
Canada, the EU, Japan, Korea, Morocco, New Zealand, Singapore, and the United States, does
allow parties to enforce their national trademark law against goods-in-transit, thereby potentially
endangering certain generic shipments2 (USTR, 2011).
In any case, there are ambiguities in determining trademark infringement. U.S. law, for
example, determines trademark infringement based on likely consumer confusion, something the
13 federal circuits employ 13 different multifactor tests to identify (Beebe, 2006). Drug
trademarks can be contentious when companies register trademark names similar to the non-
proprietary name (as in the case of Amoxil and amoxicillin), and when drug manufacturers
attempt to trademark characteristics such as color.
TRIPS requires World Trade Organization (WTO) member countries to treat “willful
trademark counterfeiting … on a commercial scale” as a criminal offense3 (Clift, 2010). This
kind of crime may be different from the civil offense of trademark infringement, if the
willfulness of the crime is unclear, for example, or if the trademark is not identically copied
(Clift, 2010). These distinctions are not important to some stakeholders. As a 2011 Oxfam policy
paper explained, “whether a falsely labeled, substandard, or unregistered product is also the
result of willful trademark infringement on a commercial scale, as criminalized under the TRIPS
Agreement, is irrelevant from the perspective of public health” (Brant and Malpani, 2011, p. 23).
Oxfam’s point is well taken. The goals of patent and trademark law are not those of
public health. Trademarks can give an incentive to invest in quality and cultivate a brand
loyalty, but this depends on consumers evaluating quality correctly, something difficult to do
with medicines (Landes and Posner, 1987). The inability of the consumer to evaluate drug
quality is the reason why medicines quality is monitored by an independent, government
regulatory agency. The courts enforce trademark and patent laws; drugs regulators enforce
quality standards. It is unreasonable and unfair to mix those jobs. Such was the logic of the
International Negotiating Body on a Protocol on Illicit Trade in Tobacco Products, which
recently removed all references to counterfeits from its treaty, noting that decisions about
trademark infringement in tobacco products was not within their purview (New, 2012).
The committee recognizes that many poor quality medicines also infringe on registered
trademarks. At times, trademark infringement can become a public health problem, but it is not a
public health problem in itself, even in so much as it pertains to medicines.
Competing Meanings of the Term Counterfeit
The contentious history of drug patent and trademark enforcement colors discussions of
drug quality, particularly the use of the term counterfeit. The U.S. Code, the WTO, the TRIPS
Agreement, and Oxfam all use the legal meaning of a counterfeit medicine as one that infringes
on a registered trademark (Brant and Malpani, 2011; Clift, 2010; WTO, 1994, 2012).
Nevertheless, the word counterfeit, like material and harmless, means one thing to lawyers and
judges and something else in common discourse. It is the widely used common meaning of
counterfeit “made in exact imitation of something valuable with the intention to deceive or
2
Anti-Counterfeiting Trade Agreement (ACTA). October 1, 2011.
3
TRIPS: Agreement on Trade-Related Aspects of Intellectual Property Rights, Apr. 15, 1994, Marrakesh
Agreement Establishing the World Trade Organization, Annex 1C, THE LEGAL TEXTS: THE RESULTS OF THE
URUGUAY ROUND OF MULTILATERAL TRADE NEGOTIATIONS 320 (1999), 1869 U.N.T.S. 299, 33 I.L.M.
1197 (1994).
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INTRODUCTION
defraud” (Oxford Dictionaries, 2012) that inspires the way the term is used by the WHO, the
Pharmaceutical Security Institute, the Council of Europe, and the governments of India, Kenya,
Nigeria, Pakistan, and, in some cases, the United States (see Table 1-1). The WHO definitions of
counterfeit lean on the intent to deceive; Table 1-1 shows how most WHO definitions use the
words “deliberately and fraudulently mislabeled.”
There is elegance to a definition that stresses the intention to deceive. Its proponents
rightly observe that this is what most people understand the word to mean anyway. This
definition has at its center the effort to distinguish between deliberate and accidental problems.
The manufacturer is not to blame if a drug is sold after the expiry date or if it has been kept in
conditions that encourage rapid degradation. The 2008 contamination of Baxter heparin was a
reminder that even expert companies sometimes produce bad products, but the failure is not
intentional (Attaran and Bate, 2010). The regulatory system typically punishes these mistakes,
while law enforcement system punishes intentional crimes.
In practice, however, it is extremely difficult to distinguish accidental and intentional
problems in drug manufacture. Making the distinction, like determining trademark infringement,
is a matter for the courts. Furthermore, competing meanings of the word counterfeit—one
narrow, meaning infringement on a registered trademark, and one broad, meaning intentionally
deceptive—frustrate many.
When bad drugs are all called counterfeit, some see in this definition an attempt to
conflate the enforcement of intellectual property rights and protection of public health (Brant and
Malpani, 2011; Clift, 2010; MSF; Oxfam International, 2011; TWN, 2010). International NGOs,
such as Oxfam and MSF, are concerned with access to medicines in the world’s poorest
countries, access that cannot be possible without the generics companies that produce medicines
for a fraction of the cost innovator companies charge. Generics companies may be vulnerable to
accusations of trademark infringement or even deception. When a generic and an innovator drug
company market bioequivalent medicines under similar sounding names or with similar looking
pills it is debatable whether or not these characteristics are copied or made with an intention to
deceive the consumer. These are questions for the courts to decide case by case.
Counterfeit is a word that almost everyone uses to talk about bad medicines, but as
Tables 1-1 and 1-2 indicate, often with widely divergent meanings. The ambiguity confuses
discussions even within governments. The FDA, for example, endorses on its website a
definition different from that in the U.S. Code or that used by the Department of Justice and
other U.S. government agencies. The use of the word counterfeit to describe any poor quality
drug does not serve the cause of intellectual precision or productive discussion. The committee
accepts the narrow, legal meaning of a counterfeit drug as one that infringes on a registered
trademark. Trademark infringement is not a problem of public health concern, nor, in most cases,
is it even readily identifiable. Drug companies, both innovator and generic, have the legal right to
challenge counterfeiting; sorting out the nuances of trademark infringement should be left the
courts.
This report is about drug quality as a public health problem; it is not concerned with
trademark infringement. Therefore, this report does not discuss the problem or solutions to the
problem of drug counterfeiting, or make mention to counterfeit drugs, except in cases where to
do otherwise would be a misrepresentation of someone else’s work. Scientific literature and
public health campaigns, especially those more than 2 or 3 years old, often describe poor quality
drugs as counterfeit. The committee hopes that all parties will break this habit, but believes that
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COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS
most speakers who use the term use it broadly with no ulterior motives or ill will towards
generics.
Substandard and Falsified Drugs
Use of the term substandard is less controversial (see Tables 1-3 and 1-4). There is
consensus among most organizations that substandard drugs are those that fail to meet
established quality specifications. When a regulator approves a drug, they approve a quality
standard, outlined in the accepted pharmacopeia or in the manufacturer’s approved dossier. As
the WHO explains, substandard products “do not meet the quality specifications set for them in
national standards” (WHO, 2009).
As Table 1-3 indicates, the emphasis on national standards is a relatively recent change to
the definition of a substandard drug. Before 2009, the emphasis was on an official pharmacopeia,
not the national standard. Critics of the addition point out that the regulatory authority is
responsible for approving national drug standards, a job that exceeds its capacity in many low-
and middle-income countries (Ravinetto et al., 2012). Accepting the national standard might
appear to endorse multiple, possibly inadequate standards (Ravinetto et al., 2012).
On the other hand, an emphasis on national standards improves the precision of the
definition. There are many internationally accepted pharmacopeias; some give, for example,
different acceptable ranges for drug concentration.4 The committee agrees with the WHO’s 2009
revision to the definition substandard to specify the standards authorized by the national
regulatory authority. It is more practical to let the national regulatory authority name the standard
for a drug and test against that standard. In any case, most countries use standards set out in the
large, international pharmacopeias. More than 100 nations, including most of the
Commonwealth, accept British Pharmacopoeia standards (GIZ, 2012); 140 recognize the U.S.
Pharmacopeia (USP, 2013), and 37 the European Pharmacopoeia (Council of Europe, 2013).
(Some countries reference different pharmacopeial standards for different drugs, and may
therefore officially use more than one pharmacopeia.)
Some understandings of a substandard medicine emphasize the manufacturer’s market
authorization. (See Table 1-3.) This distinction becomes important when a substandard product is
found in commerce. The regulatory agency can then take corrective action with the manufacturer
and recall other products from the same batch. During this process, the manufacturer may prove
with verified records and batch samples that the poor quality drug is not in fact its own. In such a
case, the manufacturer is the victim of fraud. The drug in question was falsified and therefore in
the domain of law enforcement.
The committee considers a drug falsified when there is false representation of the
product’s identity or source or both. Falsified medicines may contain the wrong ingredients in
the wrong doses. A fake product in legitimate packaging is falsified, as is a good quality product
in fake packaging (EMA, 2011). The producer’s intention is theoretically important to the
understanding of a falsified drug, though in practice it is often impossible to known what these
intentions were. That is, when a licensed manufacturer makes bad drugs, the deliberateness of
4
For amodiaquine hydrochloride tablets, the acceptable drug concentration range under U.S. Pharmacopeia is 93
percent to 107 percent of labeled amount (USP, 2011a); under International Pharmacopoeia it is 90 percent to 110
percent (WHO, 2011c). For quinine sulfate tablets, the acceptable drug concentration range under U.S.
Pharmacopeia is 90 percent to 110 percent of the labeled amount (USP, 2011b); under British Pharmacopoeia, it is
95 percent to 105 percent (British Pharmacopoeia, 2012).
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INTRODUCTION
the mistake is at least debatable. When an underground producer makes a bad quality product
there is not even a pretense of adhering to drug quality standards. This understanding of a
falsified medicine is consistent with the broad definition of counterfeit used by WHO and other
organizations. A falsified drug may also be called fake, a synonym used in this report and by
some scholars, governments, and international NGOs (Bate, 2011; Björkman-Nyqvist et al.,
2012; MSF, 2009; Newton et al., 2011). (See Table 1-5.)
Often the difference between a substandard and a falsified medicine is the difference
between a known and unknown manufacturer. Manufacturers may produce substandard drugs
because they failed to adhere to good manufacturing practices or because their internal quality
systems failed. Degraded or expired products are also substandard; in some ways, failure to pull
these drugs from the market is a quality system failure. Inspection of the manufacturer’s records
can usually distinguish between a degraded or expired drug and one that left the factory already
outside of specifications.
Falsified drugs are usually also substandard. Drug regulators have no authority over
underground manufacturers; nothing can be said about their quality controls or adherence to
good manufacturing practices. It is unlikely, though not unheard of, that an illegal manufacturer
would go to the trouble of making a quality-controlled medicine from quality-assured substrate.
The Indian generics house V.S. International’s authentic ciprofloxacin (left) and a falsified version (right).
SOURCE: (Bate, 2012b).
Distinguishing between falsified and substandard drugs is a necessary first step when
discussing the problem in any depth. It is admittedly something of an academic exercise, though.
In many parts of the world, drugs are sold without proper packaging and emphasis on label
claims has no practical value. Details of the pharmacopeial standard can also cause confusion.
The U.S. Pharmacopeia, for example, gives a dissolution standard; the British Pharmacopeia,
widely used in the Commonwealth, often does not (Paleshnuik, 2009; The British
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COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS
Pharmacopoeia). A drug that does not dissolve is substandard nonetheless. Critics of these
definitions might also point out that drug labels usually reference the pharmacopeial standard.
Therefore failing to meet the standard is also a false representation.
The definitions proposed can inevitably be caught on exceptions, but the committee
believes that public discourse is best advanced by considering two main types of bad drugs:
falsified and substandard. This report aims to set out useful, general terms for public discussion.
Defining the products of interest is valuable only in so much as it advances the discussion of the
root causes and solutions of the problem; making definitions is not an end to itself.
Similarly, the lumping together of many competing and contradictory terms with
unwieldy acronyms such as SSFFC (short for substandard, spurious, falsified, falsely labeled,
and counterfeit) only encourages confusion. Speakers seeking a parent category for substandard
and falsified drugs could consider illegitimate or even bad, but not SSFFC (Attaran et al.,
2012b).
The Problem of Unregistered Medicines
Medicines registration is one of the main responsibilities of a drugs regulatory authority
(Ratanawijitrasin and Wondemagegnehu, 2002), which maintains the medicine register, “a list of
all the pharmaceutical products authorized for marketing in a particular country” (WHO, 2011b).
The regulatory authority issues a market authorization, proof of entry to the medicines register,
to the manufacturer of any medical product sold or distributed free in a given country (SADC,
2007). Market authorization documents usually include the name and address of the
manufacturer, and information about the registered product (SADC, 2007).
Maintaining an accurate medicines register is difficult in developing countries where the
regulatory authority is often under staffed and under funded (IOM, 2012; Ratanawijitrasin and
Wondemagegnehu, 2002). To complicate the problem, medicines travel quickly among small,
landlocked countries with porous borders. The WHO found about 1,000 unregistered drugs on
the Cambodian market, for example (Lepakhin, 2003). The amount of unregistered products on
the market is also unpredictable. Sometimes bilateral trade negotiations end in large shipments of
unregistered medicines in a country (Morris and Stevens, 2006; Newton et al., 2010).
In a conceptual illustration of the problem, Attaran and colleagues show that unregistered
drugs may be of good quality (see Figure 1-1). This figure shows drug quality standards on the y-
axis and registration on the x-axis. In this framework, drugs that fail to meet the regulatory
authority’s standards are divided into failures of negligence (substandard drugs) and willful
failures (falsified drugs). This diagram separates the good quality unregistered medicines from
other types of illegitimate drugs. In practice, however, the distinction is not always clear.
Some research suggests that unregistered medicines are can be dangerous. A field survey
of uterotonic drug quality in Ghana found that all unregistered drug samples tested were
substandard; one of the unregistered products contained no active ingredient at all (Stanton et al.,
2012). Many of the samples might have degraded during disorganized transport, but the
explanation is never clear with unregistered drugs.
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INTRODUCTION
FIGURE 1-1 A two-dimensional description of medicine quality and registration.
SOURCE: (Attaran et al., 2012a). Reprinted with permission from BMJ Publishing Group.
Unregistered medicines are vulnerable to quality failures. They do not enter the market
through reputable channels and are often transported under poor conditions. These problems can
easily go undetected. Postmarket surveillance is, by definition, a way to monitor the safety of
those drugs authorized for a particular market. Therefore, the quality failures of unregistered
medicines resist detection in postmarket surveillance (Amin and Snow, 2005). The proliferation
of unregistered medicines suggests problems with the market authorization process in a country
and, more generally, with regulatory oversight. Although unregistered drugs are not by definition
falsified or substandard, they are conceptually related and part of the problem.
A Proposed Vocabulary
The lack of a consistent vocabulary has held back public discourse on the problem of
poor quality medicines in the market. As Tables 1-1 through 1-5 indicate, different countries
often have widely different interpretations of the same terms, creating a confusion that holds
back international cooperation (Clift, 2010). Defining a common vocabulary is important not just
for this report, but for all discourse on the topic.
Box 1-2 presents the definitions of the terms falsified, substandard, counterfeit, and
unregistered used in this report. As this chapter explains, distinguishing between substandard and
falsified medicines in the field can be difficult. In practice, there is often considerable ambiguity
in real-life examples of unlabelled, poor quality drugs. Nevertheless, falsified and substandard
are good categories to describe problems with poor quality drugs. Consistent use of these terms
would ease the measuring of trends, analysis of causes, and discussion of proposed solutions to
the problem.
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TABLE 1-5 Other Terms of Interest
Organization Term Definition
Oxfam Falsified Medicines for which the identity, source, or history was misrepresented (Parent category for fake and falsely labeled) (Brant and Malpani,
2011).
Falsely labeled The true properties of the product do not correspond to the information provided (Brant and Malpani, 2011).
Fake Does not contain the correct type of concentration of active and/ or other ingredients (Brant and Malpani, 2011).
EMA Falsified “Falsified medicines are fake medicines that pass themselves off as real, authorized medicines. Falsified medicines may:
contain ingredients of low quality or in the wrong doses;
be deliberately and fraudulently mislabeled with respect to their identity or source;
have fake packaging, the wrong ingredients, or low levels of the active ingredients.
Falsified medicines do not pass through the usual evaluation of quality, safety and efficacy, which is required for the European Union
(EU) authorization procedure. Because of this, they can be a health threat” (EMA, 2012).
Brazil Falsification of “Illicit reproduction of registered medicine, made by [a] third [party], with the fraudulent intention of giving a legitimate appearance of
medicines what is not legitimate” (Anvisa, 2006).
Adulteration “Intervention of [a] third [party], with the purpose of altering legitimate medicine in [a] way to commit therapeutic effectiveness and/or to
turn it noxious to the health; or intervention that modifies the specifications of the registration fraudulently, changing its registered
formulation” (Anvisa, 2006).
Alteration “Modification for addition or subtraction of components of the medicine and/or if the pharmaceutical formula, without previous and
expressed approval of the National Agency of Health Surveillance” (Anvisa, 2006).
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INTRODUCTION
Council of the Falsified “Falsified medicinal product [is] any medicinal product with a false representation of:
European Union a) its identity, including its packaging and labeling, its name or its composition as regards any of the ingredients including
excipients and the strength of those ingredients;
b) its source, including its manufacturer, its country of manufacturing, its country of origin or its marketing authorization holder;
or
c) its history, including the records and documents relating to the distribution channels used.
This definition does not include unintentional quality defects and is without prejudice to infringements of intellectual property rights.”a
Thailand Deteriorated “The following are deteriorated drugs:
Drugs 1. A drug the expiry date of which as shown on the label has been reached.
2. A drug which has so denatured as to have the characteristics of a fake drug.” b
Fake “The following drugs or substances are fake drugs:
1. A drug or substance which is wholly or partly an imitation of a genuine drug;
2. A drug which shows the name of another drug, or an expiry date which is false;
3. A drug which shows a name or mark of a producer, or the location of the produce the drug, which is false;
4. Drugs which falsely show that they are in accordance with a formula which has been registered; and
5. Drugs produced with active substances which quantity or strength lower than the minimum or higher than the maximum
standards prescribed in the registered formula by more than twenty percent.”c
India Misbranded “A drug shall be deemed to be misbranded—
a) if it is so colored, coated, powdered or polished that damage is concealed or if it is made to appear of better or greater
therapeutic value than it really is; or
b) if it is not labeled in the prescribed manner; or
c) if its label or container or anything accompanying the drug bears any statement, design or device which makes any false
claim for the drug or which is false or misleading in any particular.”d
Adulterated “A drug shall be deemed to be adulterated,—
a) if it consists, in whole or in part, of any filthy, putrid or decomposed substance; or
b) if it has been prepared, packed or stored under insanitary conditions whereby it may have been contaminated with filth or
whereby it may have been rendered injurious to health; or
a
Directive 2011/62/EU on the 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 [2011] OJ L174/77-78.
b
Thailand Drug Act, B.E. 2510 (1967). (Thailand). Chap. VII. Sec. 75.
c
Thailand Drug Act, B.E. 2510 (1967). (Thailand). Chap. VII. Sec. 73.
d
The Drugs and Cosmetics Act and Rules. (India). As corrected up to 30th April, 2003. Chap. III. 9C.
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COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS
c) if its container is composed in whole or in part, of any poisonous or deleterious substance which may render the contents
injurious to health; or
d) if it bears or contains, for purposes of coloring only, a color other than one which is prescribed; or
e) if it contains any harmful or toxic substance which may render it injurious to health; or
f) if any substance has been mixed therewith so as to reduce its quality or strength.”e
e The Drugs and Cosmetics Act and Rules. (India). As corrected up to 30th April, 2003. Chap. III. 9A.
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INTRODUCTION
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