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Substandard and counterfeit medicines:
a systematic review of the literature
Tariq Almuzaini, Imti Choonara, Helen Sammons
To cite: Almuzaini T,
Choonara I, Sammons H.
Substandard and counterfeit
medicines: a systematic
review of the literature. BMJ
Open 2013;3:e002923.
doi:10.1136/bmjopen-2013-
002923
▸
Prepublication history and
additional material for this
paper is available online. To
view these files please visit
the journal online
(http://dx.doi.org/10.1136/
bmjopen-2013-002923).
Received 28 March 2013
Revised 10 July 2013
Accepted 11 July 2013
Academic Division of Child
Health, University of
Nottingham, Derbyshire
Children’s Hospital, Derby,
UK
Correspondence to
Tariq Almuzaini;
mzxta@exmail.nottingham.
ac.uk
ABSTRACT
Objective:
To explore the evidence available of poor-
quality (counterfeit and substandard) medicines in the
literature.
Design: Systematic review.
Data sources: Databases used were EMBASE,
MEDLINE, PubMed and the International
Pharmaceutical Abstracts, including articles published
till January 2013.
Eligibility criteria: Prevalence studies containing
original data. WHO definitions (1992) used for
counterfeit and substandard medicines.
Study appraisal and synthesis: Two reviewers
independently scored study methodology against
recommendations from the MEDQUARG Checklist.
Studies were classified according to the World Bank
classification of countries by income.
Data extraction: Data extracted: place of study; type
of drugs sampled; sample size; percentage of
substandard/counterfeit medicines; formulations
included; origin of the drugs; chemical analysis and
stated issues of counterfeit/substandard medicines.
Results: 44 prevalence studies were identified, 15 had
good methodological quality. They were conducted in
25 different countries; the majority were in low-income
countries (11) and/or lower middle-income countries
(10). The median prevalence of substandard/counterfeit
medicines was 28.5% (range 11–48%). Only two
studies differentiated between substandard and
counterfeit medicines. Prevalence data were limited to
antimicrobial drugs (all 15 studies). 13 studies
involved antimalarials, 6 antibiotics and 2 other
medications. The majority of studies (93%) contained
samples with inadequate amounts of active ingredients.
The prevalence of substandard/counterfeit
antimicrobials was significantly higher when purchased
from unlicensed outlets ( p<0.000; 95% CI 0.21 to
0.32). No individual data about the prevalence in upper
middle-income countries and high-income countries
were available.
Limitations: Studies with strong methodology were
few. The majority did not differentiate between
substandard and counterfeit medicines. Most studies
assessed only a single therapeutic class of
antimicrobials.
Conclusions: The prevalence of poor-quality
antimicrobial medicines is widespread throughout
Africa and Asia in lower income countries and lower
middle-income countries . The main problem identified
was inadequate amounts of the active ingredients.
INTRODUCTION
Counterfeiting in pharmaceutical products
is an increasing worldwide dilemma with a
profound impact on lower income countries
(LIC) and lower middle-income countries
(LMIC).
12
It is also becoming an issue in
high-income countries (HIC).
3–5
There is no clear, agreed international defin-
ition of counterfeit medicines.
6
The most
widely used definition in the literature, in the
last two decades, is that given in 1992 by the
WHO.
7
This defines a counterfeit medicine as
a medicine which is deliberately and fraudu-
lently mislabelled with respect to identity and/
or source. Counterfeiting can apply to
branded and generic products. Counterfeit
products may include the following: the
correct ingredients, the wrong ingredients, no
active ingredients, insufficient ingredients or
ARTICLE SUMMARY
Article focus
▪ To systematically review prevalence studies on
substandard and counterfeit medicines published
in the literature.
Key messages
▪ The prevalence of substandard/counterfeit anti-
microbials is high throughout Africa and Asia in
lower income countries and lower middle-income
countries.
▪ The prevalence of substandard/counterfeit medi-
cines was significantly higher in the unlicensed
markets.
▪ Inadequate amounts of active ingredients were
the largest problem identified.
Strengths and limitations of this study
▪ The article demonstrates a systematic review of
prevalence studies on substandard/counterfeit
medicines, with assessment of their quality
before inclusion.
▪ This review is limited by the methodology used
in the included studies, such as sampling
methods, the assessment of a single therapeutic
class (antimicrobial drugs), as well as scarce
packaging analysis data to differentiate between
counterfeit and substandard medicines.
Almuzaini T, Choonara I, Sammons H. BMJ Open 2013;3:e002923. doi:10.1136/bmjopen-2013-002923 1
Open Access Research
fake packaging (ie, misleading about its origin or authenti-
city).
7
Substandard medicines are defined as genuine
medicines which have failed to pass the quality measure-
ments and standards set for them. These quality standard
tests have been derived from the official pharmacopoeias.
8
In 2011, the WHO member states chose to include coun-
terfeit and substandard medicines under the new term
‘substandard/spurious/falsely-labelled/falsified/counter-
feit medical products’ (SSFFC). This new term, however,
has been questioned recently
6
as it is felt not to distinguish
sufficiently between the different illegitimate drug categor-
ies (such as counterfeit and substandard) that require dif-
ferent monitoring and solutions.
According to The Pharmaceutical Security Institute
data, the incidents of counterfeit medicines increased
dramatically from 196 incidents in 2002 to 2018 inci-
dents in 2012.
9
The data are, in part, a reflection of
adequate law enforcement and regulatory oversight in
countries where these reports came from.
10
However,
this figure would be even higher if resource-poor coun-
tries had adequate surveillance systems. Drug regulatory
authorities and pharmaceutical companies hold records
on counterfeit medicines, yet most are inaccessible.
610
More insight into the problem can be gained from
prevalence studies published in the literature.
10
Thus,
our objective was to systematically review prevalence
studies published in the literature.
METHODS
A literature search was carried out using the following
medical databases: EMBASE (data range 1974–January
2013), MEDLINE (data range 1948–January 2013),
PubMed (data range 1950–January 2013) and
International Pharmaceutical Abstracts (data range
1970–January 2013). A preliminary search for MeSH
terms associated with published prevalence studies was
conducted trying to choose the most specific and sensi-
tive words for the search strategy. Specific therapeutic
areas, such as antimalarials, were recognised and added
as additional terms to increase sensitivity; the search,
however, was not limited to these categories. The search
terms included: ‘fake’, ’counterfeit’, ‘substandard’ or
‘falsified’ and have been combined with ‘drugs’, ’medi-
cines’, ‘pharmaceuticals’, ‘antimicrobials’, ‘antimalarials’
or ‘antibiotics’. The search strategy is detailed in online
supplementary table S1. The review was performed in
accordance with the PRISMA statement.
11
The eligibility criteria were any studies (irrespective of
language) that evaluated the prevalence of substandard
or counterfeit medicines within a defined area. Studies
which discussed analytical methods for the identification
of these drugs as well as reviews, opinion papers, letters
and comments were set as exclusion criteria.
Data collection process and data items
All abstracts were screened and evaluated against the
inclusion and exclusion criteria. Where there was a
doubt or the abstract was not available, the full text was
obtained to determine inclusion. Full articles were then
retrieved and a manual search of the references was per-
formed. The following data were extracted independ-
ently (TA): place of the study; type of drugs sampled;
sample size; percentage of counterfeit/substandard
medicines; dosage forms included the following: chem-
ical analysis; origin of the drugs and stated issues of sub-
standard/counterfeit medicines (defined in online
supplementar y table S2). The number of medicines
sampled and those that failed quality tests were also
extracted from studies that included samples from
licensed outlets (ie, public and private sectors) and
unlicensed outlets (ie, informal markets). Study selec-
tion and data extraction were double-checked independ-
ently (HS) before inclusion.
Studies were classified according to the World Bank
classification of income level as follows: LIC, LMIC,
upper middle-income countries (UMIC) and HIC.
12
Any
study that contained information on more than one
country was classified in the mixed group.
Substandard and counterfeit medicines are both
recognised as poor-quality medicines. Chemical and
packaging analysis is required to conclude if a medicine
is substandard or counterfeit. This, however, is difficult
and rarely reported.
13
Therefore, the term substandard/
counterfeit medicine is used in this review unless studies
formally assessed packaging to differentiate medicines
into these two different categories.
Quality evaluation assessment
Quality assessment of studies was conducted to try to
minimise bias from the methodology used to collect
data. The methodology of all identified studies were
assessed against 12 criteria adapted from a previous pub-
lished review (box 1).
14
These criteria were given in the
methodology section of the MEDQUARG (Medicine
Quality Assessment Reporting Guidelines) Checklist of
items to be addressed in reports of surveys of medicine
quality. Two reviewers (TA and HS) perform ed the
Box 1 Quality assessment criteria
1. Timing and location of study clearly stated.
2. Definition of counterfeit or substandard medicines used
mentioned.
3. Type of outlets sampled.
4. Sampling design and sample size calculation described.
5. Type and number of dosage units purchased per outlet.
6. Random sampling used.
7. Information on who collected the samples (were mystery
shoppers applied?)
8. Packaging assessment performed.
9. Statistical analysis described.
10. Chemical analysis clearly described.
11. Details on method validation.
12. Chemical analysis performed blinded to packaging.
2 Almuzaini T, Choonara I, Sammons H. BMJ Open 2013;3:e002923. doi:10.1136/bmjopen-2013-002923
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evaluation independently. If there was any disagreement
level, an independent third person (IC) was consulted.
As there has been no cut-off limit specified, all studies
that scored 6 or more were included as a subset of the
studies that have good methodological strength, and
therefore there was less chance of bias in their results.
Statistical analysis
The median prevalence of substandard/counterfeit
medicines was analysed for each income level group.
Comparison of the prevalence in licensed (public and
private sectors) and unlicensed (informal markets)
outlets was performed using the Fisher exact test for
proportions. A significant difference was defined at a
p value <0.05.
RESULTS
A total of 44 studies of the prevalence of substandard/
counterfeit medicines were identified. The number of
articles screened and assessed is detailed in figure 1.
After independent assessment, there was a 95% agree-
ment level between the two assessors against the criteria
specified for the quality assessment of the study method-
ology (box 1). No study fulfilled all 12 criteria. One study
met 10 criteria, whereas 29 studies met only 5 criteria or
less (figure 2 and online supplementary table S3).
Fifteen studies fitted the prespecified criteria of scoring
6orabove
15–29
and were included in the analysis.
Study methodology
All studies were designed to select drug samples from a
target geographical region. These included drugs
Figure 1 Flow diagram of search and review process.
Almuzaini T, Choonara I, Sammons H. BMJ Open 2013;3:e002923. doi:10.1136/bmjopen-2013-002923 3
Open Access
sampled from the public (ie, pharmacy hospitals and
primary healthcare centres), private and/or informal
(ie, market stalls and street sellers) sectors (see online
supplementary table S4).
More than half of the studies used a convenience sam-
pling method, in which investigators collected medicines
from only accessible outlets. Only four studies used
random sampling methods, in which investigators col-
lected samples from outlets that were randomly chosen
from a complete or registered list or outlets in a defined
area.
16 17 19 22
Information on the person collecting the
samples was provided by 12 studies.
15 17–23 25–28
Samples
in these studies were purchased by national collabora-
tors, behaving as normal clients, in situations where the
seller had no indication as to the purpose of the
purchases.
Methods used for drugs analysis were variable accord-
ing to the type of test, dosage form and drug analysed.
Generally, analysis of these samples was carried out with
regard to pharmacopoeia specifications (see online
supplementary table S4). Non-pharmacopoeial drugs
were analysed in accordance with specifications and par-
ticular methods of their manufactures in order to evalu-
ate the quality of these dru gs.
The majority of the studies were conducted by investi-
gators from different academic and research institutions
(60%), with 40% from multilateral organisations (eg,
WHO and UNICEF).
Overview of the studies and prevalence of substandard/
counterfeit medicines
Fifteen studies were conduc ted in 25 different countries,
mainly in Africa and Asia. Twenty-one were either LIC
or LMIC. All 15 studies assessed the quality of antimicro-
bial drugs. Antimalarial drugs were the most extensively
studied group of medicines (13 studies). Six studies
included antibiotics and two studies included other
therapeutic agents, paracetamol, ranitidine, salbutamol,
diazepam and analgesics in their sampling process.
17 23
Only two studies considered paediatric formulations (ie,
syrup and suspension) in their sampling process.
22 24
The median prevalence of substandard/ counterfeit
medicines was 28.5% (range 11–48%). The median
prevalence of substandard/counterfeit medicines for
each income level was similar in LIC (24%), LMIC (38%)
and the mixed group (28.5%; table 1). The majority of
the studies (8) were conducted in sub-Saha ran Africa,
where the prevalence of substandard/counterfeit medi-
cines ranged from 12.2% to 48% (median 34%). This
was similar in the five studies conducted in South Asia,
range 11–44% (median 22%). This prevalence is mainly
representative of antimicrobial drugs, as these accounted
for the bulk of the tested samples. Details for each indi-
vidual study are given in online supplementary table S4.
Only two studies from Southeast Asia performed pack-
aging analysis of the samples collected.
15 28
The preva-
lence of counterfeit drugs was 16% and 43% of
antimalarials, respectively. The other studies were not
designed to detect counterfeit medicines. However, the
possibility of counterfeiting was raised in five of these
studies as some of the samples had the wrong or no
active ingredients.
17 19 21–23
Stated issues of substandard/counterfeit medicines
The assessment of drugs was made through special pro-
cedures and methods derived from official pharmaco-
poeias. The most common issues with substandard/
counterfeit drugs reported by these studies are shown in
table 2. Inadequate amount of active ingredients was the
most frequent problem reported.
Prevalence according to where medicines are purchased
Where patients purchase their medicines may affect the
prevalence of substandard/counterfeit medicines. Five
studies were identified in this review that sampled from
licensed outlets (public and private sectors) and
unlicensed outlets (informal markets; table 3). Four of
these studies concerned antimalarials,
15 24 26 27
and one
concerned antibiotics.
23
The percentage of failed
samples in unlicensed outlets was 51%, whereas it was
24% in licensed outlets. The proportion of failed
samples was significantly higher in the unlicensed
markets ( p<0.000; 95% CI 0.21 to 0.32). Further details
Figure 2 Quality assessment
criteria for methodology of
included studies.
4 Almuzaini T, Choonara I, Sammons H. BMJ Open 2013;3:e002923. doi:10.1136/bmjopen-2013-002923
Open Access
on the individual failure rate in the public and private
sectors were not given in these studies.
DISCUSSION
The aim of this systematic review was to summarise the
current data in the literature regarding substandard/
counterfeit medicines around the world. The results
have shown that there is a significant problem in Africa
and Asia, in LIC and LMIC, regarding antimicrobial
medicines. Our findings highlight the lack of studies
that exist outside of these regions and therapeutic
classes. It also shows the lack of evidence available that
specifically differentiates between substandard and coun-
terfeit medicines. No individual data about the preva-
lence of these drugs in UMIC and HIC was available.
Our review shows a high prevalence of poor-quality
antimicrobials. Most of the prevalence studies focused
on antimicrobial medicines because of the considerable
burden of infectious diseases in the study countries.
This is in keeping with a recent commentary in the BMJ
that highlighted substandard medicines as a priority
area in tropical diseases.
30
Under-dosing of antimicro-
bials can enhance the survival of more resistant parasites
and therefore emergence of drug resistance.
31 32
There
was strong evidence in our results of samples with an
inadequate amount of active ingredients (93% of
studies), absence of active ingredients (47%) and dissol-
ution failure (33%), comparable to taking a medicine in
low dose and therefore likely to cause treatment failure.
If 10% of patients fail treatment, it is recommended by
the WHO that there should be a change in malaria treat-
ment policy.
33
The amount of substandard/counterfeit
medicines in the supply chain needs to be considered
prior to this happening. Studies to assess the direct link
between substandard/counterfeit drugs and drug resist-
ance, however, have not been documented.
This review has shown that the prevalence of substand-
ard/counterfeit antimicrobials reported was significantly
higher in the unauthorised market. Unofficial sale of
drugs in LIC and LMIC is a common practice and consid-
ered a serious public health problem.
21 34
Asurveycarried
out in Benin found that 86% of individuals inter viewed
thought that drugs purchased from unauthorised markets
were of good quality.
34
The high cost of genuine drugs has
been the main driving force for people to seek cheaper
drugs from unauthorised markets.
21
Gov ernments can
play an important role in this matter by reducing taxes
applied on medications. It has also to encourage domestic
manufacturing of good quality and affordable generic
drugs and to implement robust policies to ensure domestic
market utilisation of these drugs.
35 36
A large proportion of the studies identified were
found to have a poor methodological quality. Only 15 of
44 studies identified met our quality inclusion criteria.
‘Convenience sampling’ was often preferred and investi-
gators collected samples haphazardly based on what
outlets were accessible. This method is convenient and
inexpensive, and gives an initial assessment of the
Table 1 The range of the prevalence of counterfeit and substandard medicines based on the World Bank classification of
countries (by income level)
Income level
classification Countries
Number of
studies
Prevalence of substandard/
counterfeit medicines
Range % (median %)
LIC Lao PDR, Tanzania, Cambodia, Uganda 4 12.2–44.5 (24)
LMIC Indonesia, Nigeria, Cameroon 4 18–48 (38)
UMIC 0 0 —
HIC 0 0 —
Mixed group
LIC Myanmar, Cambodia, Lao PDR, Ghana, Kenya,
Tanzania, Uganda, Madagascar, Mali, Mozambique,
Zimbabwe
711–44 (28.5)
LMIC Vietnam, Thailand, Cameroon, Nigeria, Senegal,
Sudan, Armenia, Ukraine, Uzbekistan
UMIC Gabon, Azerbaijan, Belarus, Kazakhstan
HIC 0
Note: Mixed group represents the studies that have been carried out at more than one income level.
HIC, high-income countries; LIC, low-income countries; LMIC, lower middle-income countries; UMIC, upper middle-income countries.
Table 2 Frequency of six different issues reported
concerning the quality of the medicines tested
Stated problem
Frequency of studies
containing samples with
stated problem
Per
cent
Inadequate amount
of active ingredient
14 93
No active ingredient 7 47
Excessive amount of
active ingredient
640
Dissolution failure 5 33
Wrong ingredient 4 27
Impurity 2 13
Almuzaini T, Choonara I, Sammons H. BMJ Open 2013;3:e002923. doi:10.1136/bmjopen-2013-002923 5
Open Access
problem faced (analogous to a case report), but is prone
to bias and may not be representative of the target area
studied.
14
A more reliable and accurate measure involves
an estimate of a sample size and selection of a random
number of outlets from a complete list from that area.
Only four studies were randomly selecte d from a com-
plete list and only one calculated the sample size
required.
16
Information on the person collecting the
samples, what is said to retailers and the behaviour at
collection sites is also important, because if the seller
realises that the ‘customers’ are performing a drug
quality survey, this can affect their decision to offer sub-
standard/counterfeit medicines for sale. Guidelines for
surveys of the quality of medicines have been published
and give clear standards for future studies.
14
There are a number of international and national
initiatives taking place to combat the problem of coun-
terfeit and substandard medicines. INTERPOL, in
cooperation with the World Customs Organisation
(WCO) and WHO, is working with national police
forces in combating the illicit trade of medicines, target-
ing both illicit physical and online outlets.
37 38
The
Container Control Programme (CCP) established by the
United Nations Office on Drugs and Crime (UNDOC)
and WCO, to enhance inspection of containers for
counterfeit goods, has become an important tool to
counteract the traffic of counterfeit drugs.
39
Recently,
member states of the WHO have agreed on a new mech-
anism to tackle not only the problem of SSFFC but also
to ensure the availability of quality, safe, efficacious and
affordable medical products.
40 41
However, more collab-
oration between different national and international
organisations is needed to counteract this problem.
Limitations and strengths
This review has a number of limitations including only
searching published and accessible databases. Some
reports were confidential, unpublished or published solely
for limited distribution.
23
Some studies used different defi-
nitions and referred drug specifications to different phar-
macopoeias. Furthermor e, ther e hav e been inconsis tencies
in terms of drug sampling methods and the types of sector
involved. All these factors make direct comparison difficult.
Pa ckaging analysis is important to confirm if a medicine is
counterfeit or substandard. Curre ntly, there is a scarc ity of
data to measur e the pr evalenc e of each pr oblem individu-
ally. This is important as the causes and remedies are differ-
ent. All the studies involv ed antimicr obials. The prevalence
of counterfeit and subs tandard drugs in other therapeutic
classes therefore remained unclear. In addition, data ana-
lysis and samples collected by investigators in some of these
studies wer e not necessarily repr esenta t iv e of a large target
area, and thus the prevalence obtained cannot be extrapo-
lated to the whole country studied. How ev er, these s tudies
give an insight into the problem and, follo wing our assess-
ment of methodology, giv e the bes t evidence currently
available in the literat ure.
CONCLUSION
Substandard/counterfeit antimicrobial drugs represent a
huge problem throughout Africa and Asia in LIC and
LMIC, where the prevalence has been documented
within studies. Antimicrobials, in their solid formulations,
have been the most extensively studied group.
Inadequate amounts of active ingredients were the main
problem identified. Little consideration has been given
to other therapeutic classes or paediatric formulations
and this warrants further investigation. Well-designed
prevalence studies, with adequate methodological details,
are indeed required to reflect the actual prevalence.
Contributors TA and HS designed the search strategy. TA performed the
literature search, screened the titles and abstracts and managed the
references. HS independently double-checked the extracted data. TA and HS
screened the retrieved papers against inclusion criteria and independently
performed the quality evaluation assessment for the review. IC had the
original idea for the study and interpreted the results. TA drafted the
Table 3 Percentage failure of samples collected at different sectors
Country
Licensed outlets (public and private
sectors) Unlicensed outlets (informal market)
References
Total
number of
Samples
Number
of failed
samples
Percentage
of failed
samples
Total
number of
Samples
Number
of failed
samples
Percentage
of failed
samples
Cameroon, Ethiopia,
Ghana, Kenya, Nigeria,
Tanzania
240 64 26.6 27 12 44.4
26
Madagascar, Senegal,
Uganda
144 41 28.4 53 23 43.4
27
Cambodia 38 22 58 133 100 75
15
Myanmar 215 34 16 23 20 87
23
Gabon, Ghana, Kenya,
Mali, Mozambique,
Sudan, Zimbabwe
229 52 23 136 37 27
24
Total 866 213 24 372 192 51
6 Almuzaini T, Choonara I, Sammons H. BMJ Open 2013;3:e002923. doi:10.1136/bmjopen-2013-002923
Open Access
manuscript and IC and HS critically revised it. All authors approve of this final
submitted version after their revision of the manuscript.
Funding This research received no specific grant from any funding agency in
the public, commercial or not-for-profit sectors.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement No additional data are available.
Open Access This is an Open Access article distributed in accordance with
the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license,
which permits others to distribute, remix, adapt, build upon this work non-
commercially, and license their derivative works on different terms, provided
the original work is properly cited and the use is non-commercial. See: http://
creativecommons.org/licenses/by-nc/3.0/
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