Do anti-malarials in Africa meet quality standards? The market penetration of non quality-assured artemisinin combination therapy in eight African countries

Overall, non-QAACT were commonly available in the private sector and were infrequently available and distributed within the public sector. Public sector availability was typically lower than 10% with notable exceptions in the DRC (Kinshasa, 39%) and Zambia (85%). Low public sector availability is likely a result of ACT procurements supported with donor funding and therefore subject to global quality-assurance standards. In Zambia, public sector procurement of non-QAACT from 2013 to 2014 was supported in part by government funding without the restrictions placed on donor-funded commodities [36]. Private sector availability of non-QAACT was generally higher than public sector availability with the exception of Zambia. While public sector outlets may be required to obtain particular drugs that meet certain quality standards, quality may not necessarily be a factor in private sector procurement decisions. The choice to stock a particular anti-malarial is likely to be influenced by competition spurred by the stocking trends of neighboring outlets, price, consumer demand, or consumer product perceptions [37].

The AMFm, first piloted and administered by the Global Fund, was designed to increase access to affordable QAACT for private sector first-line buyers. The approach increased the availability and market share for QAACT in the private sector in countries including four of the five AMFm countries studied here: Nigeria, Kenya, Tanzania and Uganda [27]. Results from this study found higher private sector availability of QAACT as compared with non-QAACT in these four countries, and in Madagascar (also an AMFm country) and Benin (a non-AMFm country with documented private sector availability of co-paid ACT due to leakage [38]). This was not the case in Zambia and the DRC (also a non-AMFm country), where non-QAACT  availability was higher than QAACT in the private sector. One might expect AMFm countries to have relatively low non-QAACT availability, but this was not always the case. Despite improvements in private sector QAACT availability in recent years, non-QAACT availability persists and furthermore, has increased in two of the AMFm countries with notable improvements in QAACT availability: Nigeria and Kenya.

Within the public and private sectors, nine different non-QAACT were identified across study countries, with AL being by far the most common, followed by DHA PPQ. AL is the most common first-line ACT in each study country, and was one of the first ACT medicines to be developed. A proliferation of non-QA AL products, including tablets and suspensions, is therefore not surprising. Other non-QAACT are relatively new combination therapies and have few, if any manufacturers with WHO prequalification or other stringent regulatory authority approval. This includes DHA PPQ, which in 2015 was manufactured by only one company with approval from WHO/Global Fund/EMA (Sigma Tau Pharmaceuticals Inc). Numerous brands of non-QAACT were identified, coming from over 180 distinct international manufacturers. Non-QAACT were most commonly available in tablet formulation, although suspensions were not uncommon, particularly in the DRC, Nigeria and Kenya where they accounted for one-third or more of audited non-QAACT products. Suspensions are designed and marketed for small children, given the challenge of administering tablets to infants and children.

Non-QAACT were usually distributed in urban areas, and disproportionately distributed in urban areas relative to all anti-malarial distribution. Non-QAACT were typically sold by pharmacies or drug stores, depending on the country context, and these outlet types were most commonly located in urban areas. Large urban pharmacies and drug stores are likely to have fewer barriers in procuring anti-malarials [39], including fewer supply chain levels to navigate [40], allowing for better access to a variety of products. In addition, outlets in urban environments typically serve wealthier customers who may be able to better afford the relatively high price of non-QAACT.

One might have expected high relative distribution of non-QAACT to be driven by price considerations. However, results from this study show that non-QA tablets and suspensions were typically more expensive than QA AL tablets. The relatively low cost of QA first-line treatment is likely due to private sector subsidies implemented with support from the Global Fund. This copayment mechanism, first piloted as the AMFm, significantly reduced the cost of first-line QAACT in Kenya, Nigeria, Tanzania and Uganda [27]. This raises the question of why consumers would continue to pay more for non-QA products when cheaper QAACT are available. As noted earlier, products were primarily distributed by pharmacies and drug stores in urban areas, likely reflecting higher purchasing power of urban consumers. The phenomenon may be due in part to perceptions that higher prices are associated with higher quality, and/or consumer beliefs that subsidized ACT are of relatively poor quality [41], but additional research is needed to parse out purchasing determinants and consumer choice related to both price and tablet formulation. A better understanding of provider and consumer demand for QAACT and non-QAACT will be important for developing strategies to promote use of QA over non-QA products.

This study defined QAACT according to global standards and prequalification/approval from the WHO, Global Fund, or EMA. During the most recent round of data collection in 2014/2015, only 12 manufacturers met QA standards and appeared on approved/prequalified anti-malarial drug lists for the WHO, the Global Fund, and/or the EMA. In contrast, 185 manufacturers of non-QAACT were identified across the eight study countries. For some of the products currently classified as non-QAACT, there may be potential for these products to achieve QA status by extending support to manufacturers to meet requirements for prequalification.

While the WHO PQP provides guidance and support for applicants, gaining approval from an external authority is a technically challenging, rigorous process that can take a minimum of three years. Fees for the application, in-country product registration, and facility GMP inspection can exceed $100,000 [42]. Combination therapies, such as those indicated for malaria, have particularly complex testing and regulatory requirements for approval. Even after achieving QA status, products are subject to periodic testing, monitoring, and re-approval. For small or newly established in-country manufacturers with limited resources, the barriers to this assessment and approval process are often prohibitive [23, 26]. Depending on the country, quality assurance activities may or may not be well-supported by the NDRA, the country-level drug licensing, control, and post-marketing surveillance body [21]. Supporting manufacturers to obtain GMP certification and apply for WHO PQP status could leverage existing resources to increase the presence of quality-assured drugs in malaria-endemic countries. Developing and enforcing national regulations for manufacturing quality would further ensure the production and supply of quality drugs. In the case of manufacturers who have not yet reached global quality standards, working to expand capacity for quality improvement may be most appropriate. Yet, maintaining high-quality and sustainable production in SSA presents its own challenges. The unstable energy supply, lack of technical specialists, and unpredictable transport systems characteristic of some SSA countries increase the likelihood of supply chain failures and can cause production costs to balloon [43, 44]. These challenges should be taken into consideration when designing and supporting viable, high-quality manufacturing sites.

It is also important to note that non-QAACT available in non-tablet formulations are unlikely to be eligible to obtain QA status. Suspensions involve reconstitution or volume measurement and this may inhibit accurate dosing. Additionally, once opened and reconstituted, the stability and hygiene of suspension formulations can no longer be guaranteed. As such, ACT suspensions are not included on the WHO pre-qualification or Global Fund procurement lists. A preferred pediatric-friendly alternative is the use of dispersible tablets which have been available for QA AL since 2009  [45, 46, 47]. There is need for additional information on consumer and provider preferences for ACT suspensions in the context of availability of dispersible tablets. Results from this study suggest that preference for suspensions may be driving availability in both private and public sectors in some countries.

Promoting the use of QAACT and discouraging the use of non-QAACT can be addressed at the national level, and can be facilitated through exclusion of non quality-assured products from national registration lists and government procurements. NDRA lists can be used to regulate private sector outlets by promoting products on the list and implementing communication, regulation and penalties regarding the importation and sale of non-registered products. However, NDRA lists in most of the study countries are currently not well-suited to this purpose as they are generally not aligned with global quality recommendations and national treatment guidelines. Results from this study found that typically, more than half of non-QAACT available were found on national-registration lists. Aligning national drug registration with global quality assurance standards may prove challenging given the need for multi-sectoral collaboration towards this effort. Where NDRA registration lists cannot be aligned with national or global standards for quality, national malaria control programs may need to devise independent approved lists of anti-malarials for training, supervision, communication and promotion purposes.

Active efforts to remove non-QAACT from anti-malarial markets could prove challenging. Efforts may not be readily acceptable to regulatory authorities and public and private buyers that have existing agreements in place with certain manufacturers or importers. Efforts to stop the importation and distribution of non-QAACT would also have economic consequences for manufacturers themselves. Local manufacturers, which were not uncommon in the DRC and Nigeria, may be particularly vulnerable to these potential economic impacts. Furthermore, a focus on removing non-QAACT must not preclude attention to removal of banned oral artemisinin monotherapies and ineffective non-artemisinin therapies that persist on the market to varying degrees in each of the countries included in this study [48]. Removal of these products may be of more imminent concern in certain areas than removal of non-QAACT, and thus, may need to be prioritized for regulatory attention. Public health policy and regulation shifts with respect to non-QAACT would require strategies that take all of these political and economic realities into account.

Results from this study suggest the potential to substantially improve anti-malarial quality through greater private sector engagement and regulation to align private sector practices with national guidelines and quality-assurance standards. Private sector engagement to increase access to quality products can be facilitated in a variety of ways at the wholesaler and retailer level. Wholesalers, ranging from international importers to local merchandisers, can influence drug quality by restricting purchases to GMP-certified manufacturers and by monitoring products for non quality-assured drug removal. Improving private provider practices will also be an essential part of efforts to improve drug quality in the market. Strategies to improve provider practices in the private sector have included training, supervision and regulation under accreditation or other quality assurance programs. These programs are typically designed and implemented to promote the use of appropriate assessment, diagnostic/testing, referral, and treatment behaviors, including use of the first-line treatment for uncomplicated malaria, but they also provide an important opportunity for education and enforcement around non-QAACT. For example, a multi-pronged market intervention in Cambodia facilitated access to quality products through a diagnosis and treatment training for providers and through medical detailing that promoted quality assurance [49]. Tanzania’s Accredited Drug Dispensing Outlets (ADDO) pilot programme, which aimed to develop the capacity of pharmacy staff to provide quality drugs, was associated with a 13-fold reduction in unregistered medicines (from 26% at baseline to 2% after ADDO implementation) [50, 51]. Other private sector engagement initiatives, such as Nigeria’s patent medicines vendor training programme [52] and Kenya’s drug shop and clinic franchising programme [53, 54, 55, 56], have also led to quality improvement.

Results from this study show that strategies for private sector engagement and improved regulation can be highly targeted. The problem of non-QAACT availability and distribution is primarily in urban areas and is concentrated in many countries among either pharmacies or drug stores, though in other settings, private for-profit health facilities are also key outlets. Private sector engagement and regulatory enforcement focused on large urban outlets could be highly effective in removing these medicines from the market at national level. Private sector cooperation with law enforcement will be key in supporting these efforts. Conducting periodic site inspections to remove poor-quality products from the market and levying penalties for those who enable poor quality medicines to enter the market will help to improve overall market quality.

It should be noted that measures to remove non-QAACT from anti-malarial markets have the potential to reduce overall access to ACT. In the countries studied here, this is a risk primarily in the DRC, where availability of QAACT remains very low. In other study countries, particularly those with improved access to QAACT through public and private sector subsidy mechanisms, there would appear to be little to no risk in removing non quality-assured products from the shelves.

The potential to stimulate demand for QAACT at the expense of non quality-assured medicines hinges on the ability of providers and consumers to identify and demand QA medicines. One approach to branding QAACT so that communications campaigns can promote their use is to use an identifying logo or quality seal. A green leaf logo placed on product packaging and promoted in mass media campaigns was used to identify co-paid QAACT under the AMFm and the subsequent Private Sector Copayment Mechanism. Awareness of the leaf, as evidenced by increases in uptake and availability of ACT, was well documented in countries that implemented mass media campaigns to promote the brand [57‐59]. At the national level, a logo indicating quality and national approval could be applied to all QAACT and this logo could be used in campaigns to promote consumer trust and demand for these products.

An alternative to a quality logo is the use of mobile authentication systems (MAS). With MAS, scratch codes embedded on product packaging allow consumers to authenticate the product at the point of purchase via text message. Countries like Nigeria legally require all anti-malarials to carry a verifiable MAS code, which is only given to products registered with the national drug authority [60]. However, drug registration status may not be synonymous with drug quality and, until this is the case, MAS may provide a false sense of assurance for buyers. While mobile authentication has been useful for detecting falsified products and ensuring purchase of legitimate brands or nationally-registered products, it has yet to be used exclusively for product quality-assurance, such as tagging of WHO prequalified products.

The above strategies are key for reducing the penetration of non-QAACT in the market. However, they are not sufficient on their own. They must be supported by additional, complementary measures to improve anti-malarial quality such as promoting GMP, improving drug testing capacity, encouraging proper drug transport and storage, and working with law enforcement to fight falsification. Efforts to increase the share of QAACT available and distributed to consumers are equally important, and engaging the private sector in these efforts will be paramount.

Many of the strategies discussed will rely on a strong NDRA. Strengthening regulatory capacity is also key for meeting external mandates for quality approval. NDRAs in SSA suffer from a host of common structural deficiencies, including a lack of technical guidelines, a chronic shortage of qualified medicine and facility assessors, limited legislative influence, regular use of adverse event-based response rather than risk-based quality monitoring systems, a general lack of accountability, and poor regulation enforcement [21]. Some countries have already taken steps towards implementing the strategies discussed. For example, Nigeria’s National Food and Drug Administration has undertaken drug screening through deployment of drug-authenticating Raman spectrometers [61]. In East Africa, six countries have banded together to improve drug regulation through the WHO/East African Community (EAC) Medicines Regulatory Harmonization Project. Other countries in Southeast Asia have coordinated with INTERPOL, customs authorities, and police to take action against poor quality medicines [4]. While efforts have been made in the public sector to ensure availability and distribution of QAACT, more effort is needed to address the issue in the private sector. Long-term quality improvement for anti-malarials will require a cross-sector, multiple-strategy approach.