Quality of Artemisinin-based Combination Therapy for malaria found in Ghanaian markets and public health implications of their use

Though the therapeutic effectiveness of medicines to cure common tropical diseases in Africa is a poverty remedial measure, the integrity of these medicines is critical in successfully combating the diseases they target [1, 2]. Counterfeit and substandard medicines pose a stumbling block to public health delivery systems for malaria in endemic countries, [3–5]. Meta-analysis of existing data reported roughly 30 % poor quality medicines in South East Asia and sub-Saharan Africa [2].

Malaria and microbial infections are the leading causes of morbidity and mortality in Ghana [6, 7]. Malaria, alone, accounts for about 40 % of outpatient visits in the country and has significantly contributed to morbidity in all age groups [8, 9].

Concerns have recently been raised in Ghana and several other African countries about resistance to prescribed medicines for treatment of diseases [10]. Among reasons for the loss of medicines efficacy are resistance of pathogens to medicines that were previously effective; non-compliance of patients to treatment and dosage regimes and proliferation of counterfeit and/or substandard medicines [4, 11].

Since the introduction of Artemisinin-based Combination Therapy (ACT) in Ghana in 2004, there has been proliferation of different brands of ACTs on the Ghanaian market. It is perceived that some of the ACTs could be either counterfeits or substandard [12]. Surveillance on poor quality medicines could potentially be insufficient in Ghana to address this challenge, thus putting the lives of many Ghanaians at risk [13–16]. The situation is being exacerbated by the culture of indiscriminate ‘over the counter sale’ of all categories of medicine in the country [16, 17].

In response to recent reports in the Ghanaian media [18] of poor quality ACTs, we purchased following the mystery shopping strategy, all types of ACTs available in predominantly rural communities in the middle part of Ghana, in order to determine their quality using chromatographic methods established at the London School of Hygiene & Tropical Medicine (LSHTM) and the Georgia Institute of Technology, Atlanta, USA [19].

Malaria remains the most frequent reason for seeking healthcare in Ghana and registers the highest level of mortality [27]. In 2004, Ghana changed malaria policy from the use of monotherapies to ACT. This study was carried out in response to increasing anecdotal reports of substandard and counterfeit ACTs in the Ghanaian market since the start of implementation of policy changes in 2005 [28].

The prevalence of substandard ACTs was relatively high; 35.4 % of all ACTs purchased were substandard and contained less than the stated amount of API. Specifically, the majority of substandard artesunate-amodiaquine ACTs had lower than expected levels of artesunate, the more expensive API. Reasons that could have led to this high prevalence of substandard ACTs include poor compliance with Good Manufacturing Practices (GMP) and/or poor storage conditions along the supply chain. The relative contribution of these two factors could not be ascertained easily and is beyond the scope of this study.

Artemether-lumefantrine (AL) and artesunate-amodiaquine (AA) were the commonest ACTs on the market and are the ones recommended by the Ghana National Malaria Control Programme (GNMCP); however the investigators were unable to ascertain if all the brands and batches purchased in this survey had been registered with the Ghana Food and Drugs Authority (GFDA). A set of all samples of ACTs purchased have, however, been shared with GFDA. It is also possible that some of these medicines were not officially approved.

ACTs found in the Ghanaian markets are not unique to Ghana but can also be found in other malaria endemic countries. Levels of poor quality ACTs comparable to those reported in this manuscript have also been found in Asia and other parts of Africa, as wide networks and distribution channels already exist; it therefore means that issues regarding poor quality medicines are global in nature and require serious attention. Studies carried out in Southeast Asia (e.g. Cambodia, Laos, Myanmar, Thailand, Vietnam, China and Indonesia) and Africa (e.g. Senegal, Madagascar, Uganda, Burkina Faso, Nigeria and Ghana) [29–35] confirm high amounts of substandard antimalarials in circulation. Adherence to rules and regulations regarding importation and in-country manufacture of ACTs has led to minimal levels of substandard and virtually non-existence of counterfeit ACTs in countries such as Ethiopia and Rwanda [32]. The main outstanding challenge in Ethiopia has been to ensure that all medicines are registered to rule out any vulnerability towards penetration of poor quality products [32].

Recent research on ACTs has shown that products from WHO-approved manufacturers can be reported to be up to five times less likely to fail basic quality tests [36]. It is therefore important that a thorough audit be carried out on all manufacturers who are without WHO approval. A strong regulatory system is key in preventing substandard drugs entering the consumer market. In Rwanda there is an existing mandatory system for all manufacturers to provide a current WHO-approved certificate of Good Manufacturing Practice before the Ministry of Health can award contracts to those qualified to supply medicines. Rwanda uses only WHO-approved certified manufacturers [36], and this has helped in ensuring high quality standard ACTs prevail in the markets. Other countries should emulate Rwanda’s tight processes where its bureau of standards verifies, documents and together with their customs services department and ministry of health, inspects all medications imported into the country. Where poor quality medicines are found, medicine regulatory authorities partner with Rwandan police force and Interpol to target the organized criminals responsible, whenever possible. Thus, Rwanda’s drug quality control strategy depends not only on its health system, but also on its law enforcement and justice systems [37].

The sources of substandard ACTs found in the study area are global as substandard ACTs from all ACT manufacturers were observed. Substandard ACTs were identified from pharmaceutical companies in both Africa and Asia with notable countries being India, Ghana, China and Morocco (Fig. 2). A concerted effort by Ghanaian authorities will be required in this regard to drive the reduction and eventual extermination of both production and importation of poor quality ACTs.

Co-blistered artesunate-amodiaquine was the commonest ACT formulation found in the Ghanaian market. To improve on compliance, it should be the highest priority of pharmaceutical companies to replace co-blistered formulations with co-formulated ones, as patients can be selective towards the artemisinin component at the expense of the amodiaquine one, thereby increasing the likelihood of developing Plasmodium parasite strains resistant to artemisinins.[28, 38, 39].

Regional medical stores, government dispensaries and other pharmacies located in the study area were not compliant to the Ghana national drug poilcy requirements [40], as there was no thorough adherence to best practices involving the equipment, design and regular maintenance of medicine storage facilities. Records of GFDA monitoring visits in most of the facilities sampled could not be readily found. Also, some facilities had expired medicines in stock that should have been disposed of in accordance with national guidelines [40].

Proliferation of substandard ACTs into the country was observed in this survey.

When the policy and programme response against counterfeit and substandard ACTs was reviewed, it was noticed that documentations on monitoring and surveillance on medicines supply chains existed. These included procurement, storage conditions and distribution networks. The role of pharmacists, licensed chemical sellers, consumers of the medicines as well as public awareness programmes were captured in the Ghana drug and antimalarials policies as referenced in the Republic of Ghana National Drug Policy [41] as well as the Anti-malaria Drug Policy for Ghana [42].

The main reasons attributed to proliferation of substandard ACTs are lack of enforcement of drug policies by the national regulatory body and law enforcement institutions in Ghana. Resource and capacity constraints contribute to this less-than-ideal situation [43, 44]. The national borders remain porous, making it easy for importation of poor quality medicines into the country, thereby risking the lives of patients. The roles of the GFDA, Pharmacy Council of Ghana (PCG) and other authorities (including Ghana customs, Ghana police etc.) need to be more clearly defined. These agencies should be empowered to perform their roles without fear or favour.

It is promising that discussions are currently on-going among WHO-Member States about quality, safety and efficacy of antimalarials [45].

The findings of our study may seem re-assuring as no grossly counterfeit ACTs were detected. Nevertheless the high prevalence of substandard ACTs is highly concerning and should be treated with the highest public health priority. Most of the patients receiving these poor quality ACTs live in area without documented resistance to ACTs, but resistance could develop in future. Furthermore, these patients may not be appropriately treated for their illness when the need arises. Routine drug quality monitoring strategies should be put in place to gain a better understanding of the extent of the problem and changes that may occur over time, so that the malaria control programme can respond with any control measures needed. Proliferation of poor quality ACTs in malaria endemic countries has the potential for favouring selection of resistant malaria parasite species that could otherwise have been treated effectively leading to progressive loss of confidence in modern medicines by the Ghanaian populace,

No counterfeit ACTs were found when purchases were made in the studied area, however, substandard ACTs were very common. It was found that 35.4 % of the ACT medicines sampled API content. About 9 % of the ACTs for sale to community members at MOs had already expired.

Though this work was carried out in eight typical districts in Ghana, it is not expected that the results will be different in other geographical areas in the country. It can be inferred that there are major public health implications for Ghana and other malaria endemic countries with such poor quality medicines flooding the health systems. While ACTs are still highly efficacious for malaria treatment in most cases, several factors detract from their effectiveness. These not only include drug quality, but also access to ACTs, prescriber compliance, and patient adherence. In areas with high percentages of substandard or expired ACTs, there is worry that a fraction of those who have access to ACTs for treatment will not have their malaria treated appropriately, leading to continuing high levels of morbidity and mortality, loss of days at work, excessive pressure and loss of confidence on health systems, resorting to traditional remedy. All organizations and individuals championing the message of controlling, eliminating and eradicating malaria eventually need to be informed regarding the prevalence of poor quality medicines.