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Keywords:

  • counterfeit drugs;
  • Cambodia;
  • anthelminthics;
  • cross-sectional survey

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Objectives  To assess the prevalence of counterfeit anthelminthic medicines in Cambodia, and to determine influential factors.

Methods  Commonly used anthelminthic medicines were collected from private drug outlets. Medicines were carefully observed including their registration labelling, and their authenticity was investigated with the manufacturers and the Medicines Regulatory Authorities. Samples were analysed by High-Performance Liquid Chromatography at the National Health Product Quality Control Centre, Cambodia.

Results  Two hundred and three samples of anthelminthics were collected from 137 drug stores. Domestic products constituted 36.9%. Of 196 samples which were verified for registration, 15.8% were not registered. Of 165 samples successfully investigated for their authenticity, 7 (4.2%) were identified as counterfeit. All of these medicines were purchased in open packs or containers, and most of them were foreign manufactured and/or without registration.

Conclusion  The results of our survey urge strict implementation of drug registration and vigilance on the availability of unregistered medicines to combat counterfeit medicines in Cambodia.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Currently, it is not uncommon for patients to take medicines prescribed by their physician without an improvement of the condition. There could be many reasons for such a situation. In a developing country, one might wonder whether the medicines are genuine or of good quality. In severe cases, patients may die as a consequence of poor-quality or counterfeit drugs (Hanif et al. 1995; White 1999; Aldhous 2005).

‘A counterfeit medicine is one which is deliberately and fraudulently mislabelled with respect to identity and/or source’ (WHO 1999, 2009a; IMPACT 2007). Simply put, counterfeit medicines are imitations of legitimate medicines that bear the authorization of appropriate authorities. Substandard drugs, on the other hand, are legitimate drugs that do not meet the quality specifications claimed by their manufacturers (WHO 2009b). Chemical instability, inappropriate storage and transport, and poor quality control during manufacturing may deteriorate drug quality in less developed countries (Khan & Ghilzai 2007).

The severity of drug counterfeiting has been documented in a number of reports from different countries. WHO found that 20–90% of drugs were counterfeited in some African countries (Surendran 2004; Kelesidis et al. 2007). In 2005, 12.2% of antimalarials in Tanzania were identified as substandard by content analysis (Kaur et al. 2008). In southeast Nigeria, 37% of samples did not comply with standards (Onwujekwe et al. 2009), and similar scenarios exist in Asia (Newton et al. 2006; Khan & Ghilzai 2007).

Survey findings from the Ministry of Health (MoH), Cambodia suggest that 10.43% of the drugs in the country were being counterfeited in 2001 (MOH 2001). In 2004, the second survey of the MoH, Cambodia, in cooperation with WHO, reported the prevalence of 21.13% counterfeit medicines (MOH 2004). In 2006, Lon et al. (2006) found 58% counterfeit and substandard antimalarials in licensed outlets and 75% in non-licensed outlets.

Intestinal parasite infection is not uncommon in most agriculture-based developing countries, and Cambodia is no exception (Stich et al. 1999; Lee et al. 2002; Parak et al. 2004; Vuong et al. 2007). Gastroenteric infection is the 2nd leading cause of morbidity in Cambodia (WHO 2007). Substandard anthelminthics were reported in Nigeria and Sudan in 2001 (Sulaiman et al. 2001; Taylor et al. 2001). However, knowledge about the extent of counterfeiting anthelminthics in Cambodia was limited at the time. In response to the counterfeit crisis of the country, the MoH has taken several initiatives. One is a collaborative project among the MoH, Cambodia, Japan Pharmaceutical Manufacturer Association (JPMA), and Kanazawa University, Japan, which was initiated in 2006. The objectives of the project are to assess the prevalence of counterfeit pharmaceutical products and to investigate factors that influence counterfeiting. The 3rd phase of the project, started in 2008, was designed to investigate the quality of anthelminthic medicines in the country.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Study area

Samples were collected from both urban and rural areas. Seven districts (Khan) of the capital (Phnom Penh) were selected to represent urban areas, and three provinces (Kandal, Takeo and Kampong Speu) were chosen for rural sample collection. In the provinces, the sampling teams collected samples along the sides of the main national roads, where the concentration of drug outlets is greater than the other areas.

Sample collection

Albendazole, mebendazole and metronidazole were selected as candidate medicines from the Essential Drug List of Cambodia (MOH 2006b). Samples were collected from 5 to 20 August 2008 through a stratified random sampling scheme to cover all types of private drug outlets, which include licensed outlets (Pharmacy, Depot A and Depot B) and non-licensed outlets.Two teams were deployed for sampling. Each team consisted of a research investigator, one sampling officer and one sampling assistant. Medicines purchased from the same outlet and labelled with the same International Non-proprietary Name (INN), brand name, strength, size, batch/lot number, and manufacturing and expiry dates were considered as one sample. Medicine from open containers/packs was given priority over medicine from intact containers/packs. The teams collected containers or packages from most of the samples for authentication purposes. Samples were preserved at 20–25 °C until analysis.

Sample analysis

Label information on the packages and containers was cross-checked with a database prepared after collection. Photographs of each sample, its packaging and package inserts were obtained. These data were then compiled in a ‘catalogue of samples’. To verify the registration of the samples, information from the catalogue was verified with the Department of Drugs and Food (DDF), Cambodia.

Active ingredients were identified and quantified by High-Performance Liquid Chromatography (HPLC) at the National Health Product Quality Control Center (NHQC), Cambodia, according to the monogram in the United States Pharmacopeia (USP 2005). Samples were also evaluated for uniformity of weight and disintegration.

A database of manufacturer addresses was prepared using printed information, web searches, and e-mail and telephone communication. Portions of all but seven samples which lacked information were then sent to the respective manufacturers requesting verification of their products. Moreover, information on the respective manufacturers and their medicines was requested from the Medicine Regulatory Authorities (MRAs) of the manufacturing countries. Taking into account the WHO definition of counterfeit medicines, the information was then cross-checked to arrive at final comments on the authenticity of the individual medicine samples and their manufacturers (WHO 1999; Aka et al. 2005).

Data analysis

Descriptive analysis was performed using spss release 17.0.0, considering the limitations of the small sample size (SPSS Inc, Chicago). Where appropriate, Fisher’s exact test was used to test the significance of categorical variables, and Tukey’s HSD (Honestly Significant Difference) test was applied to identify associations among levels of classification variables. Statistical significance was evaluated at the 5% level.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Samples

A total of 203 samples of anthelminthic were collected from 137 drug stores in the study areas. Of these, 68 (33.5%) samples were albendazole, 56 (27.6%) were mebendazole and 79 (38.9%) were metronidazole. One hundred and one samples (49.8%) were collected from Phnom Penh, 102 (50.2%) from provinces: 65 (32.0%) from Kandal, 25 (12.3%) from Kampong Speu and 12 (5.9%) from Takeo. Domestic products constituted 36% of the total samples. A substantial fraction (30%) of the samples originated in India (Figure 1).

image

Figure 1.  Origin of the samples.

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Drug outlets

Of the 203 samples, 31.0% was collected from pharmacies, 21.2% from Depot A, 29.6% from Depot B and 18.2% from unlicensed outlets. Unlicensed outlets were significantly more common in rural (25%, 25/102) than in urban areas (12%, 12/101) (Fisher’s exact test: P < 0.05). Most of the outlets (91.9%) were staffed by one or two people (mean: 1.76, SD: 1.23, mode: 2). Pharmacists were present in only 16% (6/37) of the pharmacies at the time of sample collection, and only 2.2% (3/137) of the outlets had air conditioning.

Registration

Seven samples could not be verified for registration by DDF because of a lack of information (Figure 2). Of the 196 samples, 165 (84.1%) were registered by the authority, and 31 (15.8%) were not registered. The majority of the unregistered samples came from Depot B drug outlets (16/31, 51.6%), open containers/packs (28/31) and rural areas (22/31) (Table 1). None of the unregistered medicines were domestically manufactured. The registration status of medicines was significantly associated with the type of drug outlet (Tukey’s HSD, P < 0.05), package conditions (Fisher’s exact test, P < 0.05) and urban/rural area (Fisher’s exact test, P < 0.05). Interestingly, four of the unregistered medicines bore registration labels on their packages.

image

Figure 2.  Schematic presentation of data reduction.

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Table 1.   Registration status of medicines
FactorsNot registered/Total (%) (n = 196)
Package conditionIntact container/pack3/56 (5.4)
Open container/pack28/140 (20)
OriginDomestic0/73 (0)
Foreign31/123 (25.2)
Category of drug outletsPharmacy7/59 (11.9)
Depot A2/42 (4.8)
Depot B16/58 (27.6)
Non-licensed6/37 (16.2)
AreaUrban9/96 (9.4)
Rural22/100 (22)

Pharmaceutical quality

A total of 140 samples were analysed to measure active ingredients; all complied with the test limits of the USP monogram. All samples passed uniformity of weight assessments, and only 3 (2.14%) samples failed in the disintegration tests. A few samples were excluded from the assays because of insufficient material.

Authenticity

Authentication reports were received from 29 of 40 (72.5%) manufacturers, and 9 of 11 countries’ medicine regulatory authorities (81.8%). Seven of 165 samples (4.2%) were identified as counterfeit. Five of the counterfeit samples were labelled as being mebendazole; one was labelled albendazole, and one was labelled metronidazole. The detailed characteristics are summarized in Table 2.

Table 2.   Characteristics of counterfeit medicines
SL.Active ingredientStrength (mg)Dose formLabelled originPack/containerCambodian registration labelHPLCShop categoryRegistration status in Cambodia
1Mebendazole500TabletIndiaOpen containerNot foundPassedDepot BNot registered
2Mebendazole500TabletIndiaOpen containerNot foundPassedDepot BNot registered
3Mebendazole500TabletIndiaOpen containerNot foundPassedDepot BNot registered
4Albendazole400TabletUnited KingdomLoose medicineNot foundNot doneNon-licensed outletNot registered
5Metronidazole250TabletCambodiaLoose medicineNot foundPassedDepot ARegistered
6Mebendazole500TabletIndiaOpen containerNot foundPassedDepot BNot registered
7Mebendazole500TabletIndiaOpen containerNot foundPassedNon-licensed outletNot registered

Two of the counterfeit samples contained two types of tablets in each container. We requested the genuine manufacturers according to the information obtained from the labels and during sampling to verify the samples. Both manufacturers commented that the medicines were not authentic. One of these manufacturers is domestic, and the other is based in the United Kingdom.

According to the product labels, the five other counterfeit medicines had been produced by one manufacturer in India. One of the counterfeits had a differently coloured label on the container than that in a genuine sample of the same manufacturer. The presentation of the four other samples did not comply with the genuine samples of the manufacturer, according to their comments.

All of the counterfeit medicines were purchased loose from open packs or containers, which is 6.3% among medicines of this type. Six of seven counterfeit medicines (27.3% among non-registered authenticated) were unregistered in Cambodia. According to the product labels, all except one of the counterfeit medicines originated from outside Cambodia (one from the United Kingdom and five from India). The data are presented in Table 3.

Table 3.   Authenticity result of the samples by different factors
FactorsCounterfeit/Total (%) (n = 165)
Package conditionIntact container/pack0/53 (0)
Open container/pack7/112 (6.3)
Registration StatusRegistered1/143 (0.7)
Not registered6/22 (27.3)
OriginDomestic1/71 (1.4)
Foreign6/94 (6.4)
Category of drug outletsLicensed5/134 (3.7)
Non-licensed2/31 (6.5)
AreaUrban2/81 (2.5)
Rural5/84 (6)
Dose formCapsule0/3 (0)
Tablet7/162 (4.3)

Of 31 samples without manufacturer responses on authenticity, nine (29%) were unregistered, 28 (90.3%) were purchased from open containers/packs, 16 (51.6%) were collected from rural areas, six (19.4%) were collected from non-licensed outlets, and 29 (93.5%) originated in foreign countries.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

According to our survey, only a small proportion of the samples (36%) were of domestic origin. It could be assumed that most of the demand for anthelminthic medicines was being met by foreign manufacturers. One-third of the samples was manufactured in foreign countries and was unregistered. This finding may indicate that when there are unmet needs from internal sources and a weak enforcement of regulations, medicines can enter the country through unauthorized channels. If this is the case, then there is a strong need for well-coordinated re-enforcement of regulations among different regulatory authorities at domestic entry points.

Although the Cambodian government has recently emphasized strengthening drug regulations (MOH 2005), around half of the total drug outlets in the country are still unlicensed according to current DDF estimates (MOH 2009). During the sampling, we observed that unlicensed drug outlets had become scarce in the capital, which could have been because of the enforcement of the licensing system. Unlicensed outlets are more prevalent in the provinces, are mostly run by non-professionals and are the prime source of the health care for most impoverished Cambodians (Yanagisawa et al. 2004). These people are unfortunate in receiving poor-quality health care on the one hand and low-quality medicine on the other. In the survey, most (71%) unregistered samples were collected from Depot B and non-licensed types of outlets. According to the licensing system of DDF, a pharmacist should run a pharmacy. However, our survey found that pharmacists attend only 16% of licensed pharmacies. It could be that the pharmacist is absent from day-to-day activities and only uses his or her name to fulfil the licensing requirement. Only a few (2.2%) of the outlets had air conditioners. Yang et al. (2004) found a similar scenario during 2002–2003 in Cambodia, where the figures were 9.4% and 2.1%, respectively.

One of the limitations of our survey might be the selection of sampling areas, which may restrict the study findings to one region of Cambodia instead of to the entire country. The prevalence of counterfeit medicine in this study was 4.2%, especially for the anthelminthic categories of medicines. This finding might be much lower than the prevalence of counterfeit medicines for other anti-infective medicines (MOH 2001, 2004; Yang et al. 2004; Aldhous 2005; Lon et al. 2006). However, even a single case of counterfeit medicine is unacceptable. One of the reasons behind the current lower prevalence might be the strengthening of drug regulations in recent years, accompanied by the efforts to increase public awareness (MOH 2006c). The phenomenon could also be attributed to the ever-changing strategies of counterfeiters; they do not choose medicines where the diseases are less fatal. This discrepancy might also arise from the operational definitions of counterfeit medicines that are incompatible with the WHO definition. Unlike other studies (Yang et al. 2004; MOH 2006a), none of the medicines in our study failed in the content analyses, which may indicate that counterfeiters had become more concerned with maintaining the quality of their products (Aka et al. 2005; Amin & Kokwaro 2007) By earning the trust of the community, they could eventually gain a market share over the genuine products. As the production of counterfeit medicines is operated outside the boundaries of any regulatory system and without any quality assurance, patients are always exposed to the risks of health hazards.

All of the counterfeit medicines identified in this survey came from open containers or packs, which might raise suspicions that the original packs/containers were tampered with at some point in the distribution channel. Additionally, two of the counterfeit medicines had a variety of medicines in the same container, which clearly signifies the adulteration of contents within genuine containers. The survey was not designed to investigate the forensic evidence of the counterfeit samples; nevertheless, the inclusion of a forensic investigation in a future project might facilitate faster action against these criminal practices.

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

It is evident that counterfeit medicines among anthelminthic are prevailing in the pharmaceutical markets of Cambodia, and these medicines were more likely to be of a foreign origin and/or without registration. As all of the counterfeits found in this survey were either loose medicines or medicines in open containers/packs, there is much need to explore and improve the quality of pharmacy practices as well as the integrity of the supply chain of the medicines. A thorough implementation of medicine registration along with the collaboration of all the stakeholders is crucial to overcome this crisis.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

This survey was conducted with the financial support from the Japan Pharmaceutical Manufacturers Association (JPMA). The authors thank Mr. Seiji Miyazawa for his generous cooperation. We are grateful to Professor Tea Kim Chhay, Director, Department of Drugs and Food, Ministry of Health, Cambodia and other staff of the department who assisted in the sample collection and authenticity investigation. We gratefully acknowledge the cooperation received from the Medicine Regulatory Authorities of the manufacturing countries and all of the manufacturers of the samples.

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  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References
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