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The State of Medicine Quality in the Mekong Sub-Region

 | 
Sauwakon Ratanawijitrasin
, 
Souly Phanouvong

1 - The Mekong Subregion and Medicine Quality

Texte intégral

1.1 - Legal Framework for Medicine Quality in the Five Countries

1Substandard and counterfeit medicines exist in the Mekong Subregion despite the existence of legal frameworks and regulatory systems designed to control them. Although legal definitions and requirements of substandard and counterfeit medicines under the laws in each country might differ, these two categories of medicines both fall within the realm of regulation. The following sections provide brief reviews of the legal definitions and requirements related to medicine quality, with a special focus on substandard and counterfeit medicines, in the five countries – Cambodia, China, Lao PDR, Thailand and Vietnam.

2In Cambodia, the 1996 Law on the Management of Pharmaceuticals provides a broad framework for pharmaceutical management matters. This law grants the Ministry of Health the authority to issue instructions and control activities concerning pharmaceuticals.

3According to Cambodian law, a counterfeit drug is defined as a drug

4(1) which is deliberately produced with incorrect quantity of or wrong active ingredients, or

5(2) without active ingredients or unregistered product which amounts of active ingredients are deliberately outside the defined pharmacopoeias or accepted standard, or

6(3) which is deliberately and fraudulently mislabelled with respect to identity source or with fake packaging,

7(4) which is repacked or produced by an unauthorized person.

8A substandard drug is then defined as a registered product which its specifications are out of defined pharmacopoeias or accepted standard.

9In China, the Drug Administration Law of the People’s Republic of China, revised in 2001, provides clear definitions and conditions for the regulation and management of pharmaceutical matters. Under Article 48, the production (including dispensing) and distribution of counterfeit drugs are prohibited. The definition of counterfeit drug is clearly outlined for any of the following cases:

10(1) the ingredients in the drug are different from those specified by the national drug standards; or

11(2) a non-drug substance is simulated as a drug or one drug is simulated as another.

12Also, a drug shall be treated as a counterfeit drug in any of the following cases:

13(3) its use is prohibited by the regulations of the drug regulatory department under the State Council;

14(4) it is produced or imported without approval, or marketed without being tested, as required by this Law;

15(5) it is deteriorated;

16(6) it is contaminated;

17(7) it is produced by using drug substances without approval numbers as required by this Law; or

18(8) the indications or functions indicated are beyond the specified scope.

19Likewise, the production (including dispensing) and distribution of substandard drugs are also prohibited under Article 49. Any drug with content not up to the national drug standards is a substandard drug. In addition, the law also specifies that any drug shall be treated as a substandard drug in any of the following cases:

  1. the date of expiry is not indicated or is altered;
  2. the batch number is not indicated or is altered;
  3. it is beyond the date of expiry;
  4. no approval is obtained for the immediate packaging material or container;
  5. colourants, preservatives, spices, flavourings or other excipients are added without authorization; or
  6. other cases where the drug standards are not conformed. (Order of the President of the People’s Republic of China 2001).

20In Lao PDR, the Law on Drugs and Medical Products promulgated in 2000 defines counterfeit drug as any modern or traditional medicine that is a fake or is an imitation of a drug that is produced, distributed and legally registered (Article 11).

21A substandard drug is termed in this law as a “non-standard” drug, and is defined as any modern or traditional medicine, the composition of which is inconsistent with the drug’s registered formula (Article 12). In addition, the law also defines another category, a “deteriorated drug” as any modern or traditional medicine, the quality of which has deteriorated due to expiration or other impacts. (Article 13).

22This law also stipulates that the retail sale of drugs and medical products can only be conducted through legally licensed pharmaceutical stores (Article 26).

23In Thailand, the legal framework for drug regulation is currently provided by the long standing Drug Act of 1967 (BE 2510). Under this law, production, sale, and importation of fake drugs, substandard drugs, deteriorated drugs, unregistered drugs, drugs who had their license withdrawn for more than six months, are prohibited (Article 72). The definition of counterfeit or fake drug is clearly specified in the law (Article 73) as any drug or substance:

  1. which is wholly or partly an imitation of a genuine drug; or
  2. which shows the name of another drug, or an expiry date which is false; or
  3. which shows a name or mark of a producer, or the location of the producer which is false;
  4. which falsely shows that they are in accordance with a pharmaceutical preparation which has been registered; or
  5. which was not produced in accordance with standard such that the product contains the active ingredient in quantity or strength is lower than the minimum or higher than the maximum amount registered by more than twenty percent.

24Article 74 defines a sub-standard drug as a drug:

  1. which was not produced in accordance with standards such that the product contains the active ingredient in quantity or strength is lower than the minimum or higher than the maximum amount registered, but to a degree less than that stated in Article 73 (5) – which is that of fake drug.
  2. Produced such that the purity and other characteristics which are deemed important to its quality deviate from the criteria specified in the registered formula or the formula modified according to the Minister’s order.

25In addition, another category called “deteriorated drug” is also defined and regulated. A drug is considered deteriorated drug if:

  1. its expiry date as shown on the label has been reached;
  2. it has been denatured as to have the characteristics of a fake drug or differing from the standard under Article 74.

26In Vietnam, the current Pharmaceutical Law was adopted in 2005. Article 2 of this law specifies the terms of a substandard drug as a drug that has failed to meet the quality standards registered with the competent authorities. The same article defines counterfeit drug as a product deliberately and fraudulently made in drug form, including the following:

  1. containing no pharmaceutical substances;
  2. containing pharmaceutical substances different from those stated on the label;
  3. counterfeiting product names, industrial designs of drugs which have been already registered by other manufacturers for industrial property protection.

27Another article (Article 9) stipulates that trading in drugs of unclear origin, counterfeit drugs, substandard drugs, expired drugs, drugs in the banned list of import, drugs for clinical trials, drugs which are not permitted for marketing, sample drugs used for registration or for promotion to physicians is strictly forbidden by law. In addition, selling drugs at places that are not legally authorized to sell drugs is also a strictly forbidden act.

28Because each country may have a different legal definition for substandard and counterfeit medicines, in multi-country studies the definition developed by the World Health Organization (WHO) is usually employed. Substandard medicines are genuine medicines produced by manufacturers authorized by the appropriate national medicine regulatory authority (NMRA) but do not meet quality specifications set for them by national standards (WHO 2011).

29Substandard medicines are products whose composition and ingredients do not meet the correct scientific specifications, and which are consequently ineffective and often dangerous to the patient. Substandard products may occur as a result of negligence, human error, insufficient human and financial resources or counterfeiting.

30A counterfeit medicine, according to the World Health Organization, is one that is “deliberately and fraudulently mislabelled with respect to identity and/or sources.” Counterfeiting can apply to both branded and generic products. These products may contain correct ingredients or wrong ingredients, without active ingredients, with insufficient active ingredients or with fake packaging. (WHO 2003)

1.2 - Assessing the Quality of Medicines in the Mekong Subregion: a Brief Review of Existing Empirical Studies

31This section provides a review of existing empirical studies on medicine quality in the Mekong Region, covering Cambodia, Yunnan Province in China, Lao PDR, Thailand and Vietnam. This review is not meant to be exhaustive nor comprehensive, therefore it does not list the results of all studies. It is rather intended to highlight some of the issues and problems surrounding the quality of medicines, and when medicine quality becomes a matter of interest for intervention, e.g., monitoring their quality and taking enforcement action.

32In addition to surveys of medicine quality conducted in a specific country, there have also been studies undertaken across many countries. A multi-country study focusing on artesunate was carried out between 1999 and 2000, in which 104 samples in blister packs purporting to contain artesunate were collected from shops, pharmacies, NGOs, and hospitals in Myanmar, Cambodia, Vietnam, Lao PDR and western Thailand. Test results showed that 29% of the blister packs collected contained no detectable artesunate. All were falsely labelled as having been manufactured by Guilin Pharmaceuticals Co. – a major producer of artesunate in Asia. Of the artesunate samples bought from pharmacies and shops, 39 (38%) were counterfeit. Fakes were found in all five countries. The proportion of fake artesunate in Cambodia was reported to be 25%, Lao PDR 38%, Myanmar 40%, Thailand 11%, and Vietnam 64% (Newton et al. 2001).

Figure 1: Example of counterfeit chloroquine phosphate tablets found in Cambodia in 2004

Figure 1: Example of counterfeit chloroquine phosphate tablets found in Cambodia in 2004

Photo: M. Boravann

33Medicine quality in Cambodia has long been a concern for many parties. Since the late 1990s, many organizations monitored, using different methodologies, the quality of medicines collected from different areas of the country. Cambodia’s Ministry of Health has received support from international organizations to conduct quality surveys. Key among them are the European Commission-Cambodia Malaria Control Project (EC-CMCP), World Health Organization, and United States Pharmacopeia. Results from many studies have revealed the extent of medicine quality problems in both public and private sectors. For example, the EC-CMCP surveys, conducted during 1998-1999, found that most of the mefloquine tablets and about half of the artesunate blister packs sampled were fake medicines.

  • 3 In Cambodia, a fake medicine is a pharmaceutical product that does not contain the active pharmace (...)

34 3 A subsequent survey uncovered that fake artesunate was sold by 71% of 133 drug vendors and pharmacies in 12 market places, and fake mefloquine by 60% of those outlets (Rozendaal 2001). A WHO-funded Ministry of Health survey in 2000 collected and tested 230 samples, the majority of which were anti-infectives, from Phnom Penh markets and five provinces (Kampong Cham, Kampong Chhnang, Takeo, Kampong Speu, and Kandal). Quality tests revealed that 13% failed to meet standard. Among these, 10.4% were considered counterfeit (failed the test and not registered) and 2.6% were considered substandard (failed the test but registered) (cited in USP-DQI 2004).

Figure 2: Example of counterfeit artesunate found in the Mekong Subregion in 2004

Figure 2: Example of counterfeit artesunate found in the Mekong Subregion in 2004

Photo: T. Sovannarith

Figure 3: Example of counterfeit amoxicillin capsules found in Cambodia, 2009

Figure 3: Example of counterfeit amoxicillin capsules found in Cambodia, 2009

Photo: M. Boravann

Figure 4: Multi-colour medicine sachets of cocktail pills repacked by retail drug outlets are still available in some parts of the countries in the Mekong Subregion. This photo was taken in Cambodia in 2011.

Figure 4: Multi-colour medicine sachets of cocktail pills repacked by retail drug outlets are still available in some parts of the countries in the Mekong Subregion. This photo was taken in Cambodia in 2011.

Photo: T. Sovannarith

35Poor quality medicines in Cambodia were distributed through public, private, as well as non-governmental facilities. In a study tracing 132 samples of 14 types of medicines, most of which were again anti-infectives, 13% of the samples from public facilities, 7.7% from non-governmental organizations (NGOs)/mission facilities and 9.6% from private retail outlets were substandard (cited in USP-DQI 2004). In 2003, a USP-DQI study collected 451 drug samples from 171 outlets in Pursat, Battambong, Pailin and Preah Vihear provinces bordering Thailand and Lao PDR. The results showed that the average failure rate of quinine was as high as 71.8%, artesunate 19.8%, and tetracycline 26.6%, followed by chloroquine 8, 5% and mefloquine 7.7%. Counterfeit and substandard anti-malarials were available both in licensed and unlicensed drug outlets. Fifty-eight percent of the 38 licensed and 75% of 133 unlicensed drug outlets surveyed sold counterfeit medicines (Lon et al. 2006). Another study focusing on the quality of aspirin tablets sold in drugstores in Phnom Penh was conducted between 2002 and 2003. Aspirin tablets were purchased from 96 randomly selected drugstores, both legal and illegal, proportionally from the seven districts of Phnom Penh. Test results show that although 83.3% of the aspirin samples met the assay for content as claimed on the label, most failed dissolution test. Overall, only 7.3% passed all the test criteria (Yang et al. 2004). More recently, in July 2008, inspections carried out by the Pharmacists Association of Cambodia discovered that approximately 20-40% of medicines sampled from pharmacies in Phnom Penh were unregistered (Sovan & Yin 2008). Another report in 2009 revealed that samples of chloroquine, artesunate, quinine, amoxicillin, ampicillin, and penicillin failed laboratory testing (USP-DQI 2009). The Cambodian medicine regulatory authority has stepped up law enforcement in recent years to curb the sale and smuggling of counterfeit and substandard drugs.

36In a large country like China, findings from one geographical area can by no means represent the situation in the entire country. Documented studies in China, although few, involved larger numbers of samples in comparison to surveys conducted in other countries in the region. A 1997 report from an investigation conducted by the Ministry of Health of the People’s Republic of China indicates that, of 1100 medicines, 138 products failed to meet national standards. Among these failed medicine samples, 48 were identified as fake medicines with pirated registration numbers. Another survey carried out in 1998 found that 13.1% of the 20,000 batches tested were either counterfeit or fell below standards (cited in USP-DQI 2004). Another study by the China Food and Drug Administration examining 110,426 batches of anti-malarial medicines from nine provinces during March–August 2006 found a total of 3,122 batches to contain counterfeit or substandard medicines.

37Similar to Cambodia, attempts have been made to assess medicine quality in Lao PDR. Studies have been conducted by the Food and Drug Quality Control Center (FDQCC) in collaboration with external agencies since the early 1990s.

38Various drug quality studies found varying percentages of substandard and fake medicines. For example, studies in the first half of the 1990s found 17% of the samples substandard in one survey, 33% substandard in another, and both substandard and counterfeit medicines were identified in two other studies (USP-DQI 2004). A survey of 106 private pharmacies in Savannakhet Province in 1997 uncovered that 46% of 366 samples of four different essential medicines were substandard, with 3.3% containing no active ingredient. A follow-up survey on 92 pharmacies conducted in 1999 found a lower percentage of substandard medicines at 22%, though this is still a worrisome level (cited in USP-DQI 2004).

39A study covering a large number of about 2,300 samples collected from districts, pharmacies, and shops, using stratified random sampling methods, found that 28 of the 29 (96%) artesunate tablets collected did not contain the active ingredient (Sengaloundeth et al. 2009).

40Very limited information on medicine quality is available in Myanmar. This is not because of the absence of interest in the medicine quality situation in the country, but rather due to the political situation and international relations over the past decades. Of the few studies available, one was conducted by the World Health Organization (WHO) in 1999. This study found that 16% of the 212 samples tested for quality failed, with active ingredients below pharmacopoeial limits. Chloramphenicol preparations showed a high failure rate of 35%, followed by ranitidine at 20%, co-trimoxazole at 19%, and amoxicillin at 16% (Wondemagegnehu 1999). In another study reported in 2008, counterfeit artesunate was found in Kengtung, the capital of the Shan State, as well as along the border of Myanmar and Thailand (cited in McGinnis 2010).

41Monitoring medicine quality in Thailand has long been routinely conducted by the Thai Ministry of Public Health according to its annual plan. In addition to the internal agencies’ efforts, the Ministry also collaborates with international organizations. A 1997 study on a small number of samples (15) of anti-microbial medicines collected from pharmacies and other retailers found 40% of samples had active ingredients outside the pharmacopoeial limits, with roughly 50% of these obtained from non-pharmacy outlets (Shakoor et al. 1997). An analysis was performed on the internal test results data from the Ministry’s routine monitoring between 1990 and 2003. The results from quality tests on samples on a wide variety of medicines collected revealed that percentages of substandard medicines during those years ranged from 8.8 to 17.0% (Ratanawijitrasin 2003).

42Aside from anti-microbials, medicines for treating erectile dysfunction have been another key target of counterfeiting. A news report in 2008 indicated that of the 217 samples of Viagra purchased from Bangkok and other provinces, test results found that 202 samples were counterfeit, with only 17%-48% of the active ingredient (Bangkok Post 2008).

43In recent years, heightened law enforcement attempts have been made by the Ministry of Public Health. Crackdowns on illegal manufacturers and licensed pharmacies in Bangkok selling counterfeit medicines resulted in the confiscation of many illegal pharmaceutical products, many of them being expensive and lifestyle medicines. These included Viagra, Cialis, Levitra anabolic steroids, clindamycin, minoxidil, Nolvadex, and Finpecia (Matichon newspaper 2010, 2011a, 2011b).

44Quality control of medicines in Vietnam is performed by the National Institute of Drug Quality Control in Hanoi, the Sub-Institute of Quality Control in Ho Chi Minh City, and drug quality control laboratories in provincial health departments.

45In a 1995 post-marketing survey, 31,125 drug samples were collected from various parts of Vietnam and tested for quality. Around 5% (1,703 samples) did not meet the quality standards. Among these, 1,537 were substandard and the remaining 166 were counterfeit (USP DQI 2004). In a 1999 study conducted by WHO, 288 samples of anti-microbials (amoxicillin, ampicillin, chloramphenicol, chloroquine, metronidazole, rifampicin, and tetracycline) and other non-anti-microbial medicines were collected and tested. Results of laboratory testing showed that 22 samples did not meet the pharmacopoeial standards on active ingredients; the overall failure rate was 8% (Wondemagegnehu 1999).

46More recently, the quality of anti-epileptic medicines was surveyed. Tablets of carbamazepine, phenytoin, and valproate collected from the city of Long Xuyen (An Giang Province) were tested. It was found that only 35% of the samples met quality standards (Mac et al. 2008). In its continuing efforts to estimate the risk, the drug regulatory authority in Vietnam reported that, of the 25,460 medicine samples tested in 2007, 3.3% failed quality standards (Thanh Nien News 2008).

47As reviewed above, there have been numerous studies on medicine quality in the Mekong Region. A number of observations can be made from these existing efforts to summarize past situations and identify potential future developments. Increased interest in monitoring medicine quality in the Mekong Region generally began in the 1990s, with enhanced monitoring efforts in various countries over the past decades. The types of medicines which received the greatest interest in quality monitoring are anti-infectives. Certain groups gained special attention, for example anti-malarials and antibiotics. Findings from existing studies clearly showed that substandard and counterfeit medicines exist in all the Mekong Subregion countries. The situation of certain types of medicines and in certain areas of the region should be a cause for great concern. However, findings of poor quality medicines did not necessarily lead directly to legal enforcement or other actions by the responsible parties.

48From a methodological point of view, each of the existing studies covers a limited geographical area, and a limited number of medicines. The methodologies employed in these studies for sample collection and testing are varied. Furthermore, few attempts have been made to conduct follow-up monitoring in the areas previously studied, with the same methodologies, on the same set of medicines. With all these various findings from different methodologies, it is difficult to establish relationships between any causal factors and the quality of medicines found in a specific area or at a point in time.

49Results from each of the studies were reported separately. Most of them can be seen as separate cross-sectional findings. Piecing together these findings can only provide a very limited picture, rather than an overall view, of the quality situation in a country or the region.

50This led to attempts to “systematize” and “standardize” the methodologies for sample collection, testing, data analysis, and reporting. Examples of such efforts are documented in the following references: WHO 1999, Phanouvong et al. 2004, Newton et al. 2009, USP-PQM 2010. The efforts to monitor medicine quality and to standardize the methodologies to do so are essential in understanding and improving the quality of medicines.

51Given the current practices and knowledge, a number of suggestions can be made to help better understand the state of medicine quality as well as to make better use of such efforts. First, the monitoring of medicines quality is important to public health, as well as industry development. Such efforts should be continued and be supported. Second, systematized and standardized methodologies for medicine quality monitoring will eventually help make findings from different studies more comparable. Development of such protocols should be a collaborative effort by all the parties involved. Third, a web-based database should be developed to compile the quality findings from the different studies on the quality of medicines. This would help make better use of the findings, as well as enable cross-sectional and longitudinal analyses of the various data together, where feasible. In the sections below, framework and examples of analysis from a prototype of such database will be described. Both the standardization of methodologies and the development of database and framework for analysis will help make the costly endeavour of medicine quality monitoring more cost-effective.

52Fourth, the ultimate intended effect of all the monitoring efforts should be the reduction of substandard and counterfeit medicines in the region. This can be fulfilled when the supplies of these bad medicines can be blocked, and demand can be decreased. Therefore, systematic efforts should be made to help better understand capacity limitations in regulatory systems and related factors in law enforcement in these countries. In addition, there should also be systematic efforts to help better understand health-seeking behaviour, as well as access to medicines, of people in the Mekong Region, particularly those in areas where substandard and counterfeit medicines are rampant.

Notes

3 In Cambodia, a fake medicine is a pharmaceutical product that does not contain the active pharmaceutical ingredient of that product as claimed on the label.

Table des illustrations

Titre Figure 1: Example of counterfeit chloroquine phosphate tablets found in Cambodia in 2004
Légende Photo: M. Boravann
URL http://books.openedition.org/irasec/docannexe/image/1206/img-1.jpg
Fichier image/jpeg, 104k
Titre Figure 2: Example of counterfeit artesunate found in the Mekong Subregion in 2004
Légende Photo: T. Sovannarith
URL http://books.openedition.org/irasec/docannexe/image/1206/img-2.jpg
Fichier image/jpeg, 100k
Titre Figure 3: Example of counterfeit amoxicillin capsules found in Cambodia, 2009
Légende Photo: M. Boravann
URL http://books.openedition.org/irasec/docannexe/image/1206/img-3.jpg
Fichier image/jpeg, 99k
Titre Figure 4: Multi-colour medicine sachets of cocktail pills repacked by retail drug outlets are still available in some parts of the countries in the Mekong Subregion. This photo was taken in Cambodia in 2011.
Légende Photo: T. Sovannarith
URL http://books.openedition.org/irasec/docannexe/image/1206/img-4.jpg
Fichier image/jpeg, 84k

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