Tropical Health Matters

While some countries are being praised this week for their progress in controlling malaria, Uganda seems to be suffering from a double knock out punch when it comes to malaria financing. Challenges have appeared in both the private and public sectors.

In the most recent scorecard from the African Leaders Malaria Alliance (ALMA) scored poorly in terms of long lasting insecticide treated net distribution and low on the measure of government financial support for the health sector.

The private sector challenge has come in the form of fake medicines in local shops. This comes in the form of a threat to individuals and families who spend their hard earned cash, that is out-of-pocket expenditure (OOP) of malaria medicines that at best inappropriate and at worse are devoid of active ingredients, increasing the likelihood that the sick person will develop severe disease and maybe die.

Specifically the Washington Post reported that an indigenous medical practitioner “in Kampala, says he has seen a big increase in business as patients turned off by the prospect of dangerous fake drugs seek relief from illness.” The article explains that although “Officials and international aid agencies have long encouraged the sick to place their trust in modern medicine. But fake pharmaceuticals believed to have come from Asia have flooded” African Markets including Uganda.

The irony is that Uganda is part of the testing of the Affordable Medicines Facility malaria (AMFm) project that was supposed to drive out fake and inappropriate medicines by making low cost (subsidized) quality antimalarials available in both public and private sectors. While Uganda witnessed an increase in market share of the green-leaf branded quality assured artemisinin-based combination therapy drugs, it did not achieve other benchmarks such as supportive behavior change communication and low cost targets (mark-up averaged 133% – highest among the 8 pilots).

The second threat comes from extensive embezzlement by national malaria program staff.  Earlier this month Uganda was in the news for returning 4 million Euro of misappropriated funds to the Irish Government.

Then an ongoing investigation into embezzlement came to light a few days ago. The Observer Newspaper as shared on AllAfrica.com reported that …

“An investigation into the financial practices of officials running the ministry of Health’s Malaria Control programme (MCP) shows they forged almost everything from workshops, car hires, allowances and fuel expenses. The investigation has now shifted its focus to the extent of the forgery and theft by officials implicated in the loss of nearly Shs 78bn (US $29m). The shift in the focus of the inquiry follows a review of stacks of documents provided by three suspects involved in the MCP scandal. Police confirm that the documents show the extent of the forgery by some officials involved in the anti-malaria campaign.”

In these times when it is difficult to increase health development spending for malaria both domestically and from international donors, all efforts are needed to ensure that waste and fraud are eliminated.

When the Affordable Medicines Facility malaria (AMFm) was conceptualized, designers clearly identified several ‘supportive mechanisms’ that would be needed at the country level. In particular guidance called for “RESPONSIBLE INTRODUCTION: IN-COUNTRY SUPPORTING INTERVENTIONS” [1] in five key areas:

• National policy and regulatory preparedness
• Wholesaler incentives and pricing/margin-control mechanisms
• Public education and awareness (IEC)
• Provider training
• National monitoring and quality preparedness (resistance monitoring, pharmacovigilance, and quality surveillance)

The planners envisioned the need to, “Train health professionals and private wholesalers/retailers to promote safe and effective use of ACTs, including diagnosis, prescription, and treatment,” since many of these would be in the private and/or informal sector without the benefit of more orthodox health training or recent updated in-service training. Such training could also reinforce other supportive interventions such as consumer education and adherence to recommended pricing levels.

AMFm was designed as a two-year ‘pilot’ to determine subsidized antimalarials could get into the market – both private and public – in such a was as not only to increase overall supply of quality medicines, but also drive out more expensive and inappropriate drugs. As the project comes to a close at the end of this year, many people are looking to see if it would make a difference.

Earlier this year Yamey, Schäferhoff and Montagu [2] raised the question – what would AMFm’s success look like.  Would the subsidized quality drugs really ‘crowd out’ the costlier share of the market?  In the process they too addressed the importance of supportive interventions, noting that, “In addition to the price subsidy, the AMFm involves supportive interventions aimed at boosting ACT use, including in-country branding and associated awareness campaigns for sellers and patients, training for ACT providers and greater access to rapid diagnostic tests for malaria.”

Now a preliminary report has come out looking at the outcome issues of Artemisinin-based Combination Therapy (ACT) availability, affordability, use and market share. [3]  A key finding so far has been that, “It is notable that the major benchmarks for success for the upstream indicators of availability, price and market share of quality-assured ACTs have been met or exceeded in 6 of 8 pilot countries, particularly in light of the short implementation period.”

The Advisory group was concerned that, “the evaluated implementation period in each pilot was less than 12 months for assessing the full combined effect of the three components of the model: (i) manufacturer negotiations; (ii) buyer co-payment; and (iii) supporting interventions,” but were excited that even with such drawbacks, progress was evident.

They focused their definition of the ‘supporting interventions’ on consumer education and awareness (IEC/BCC) and provider training and observed that these were, “integral to assuring success of the program objectives of increasing availability and market share and decreasing price” of quality ACTs. They found that “Pilots with higher achievement had the following characteristics: longer period of co-paid ACTs in-country with simultaneous implementation of key supporting interventions (i.e., IEC/BCC and provider training) …”

The initial model for AMFm envisioned that almost 20% of the grant should be devoted to these supportive interventions, and the pay-off seems to be confirmed. The training component will become even more crucial as malaria rapid diagnostic tests (RDTs) become a more common part of provider skill sets, especially those in the private sector.

Not every health management problem can be solved by training and education, but the AMFm experience seems to show that these are crucial components in a comprehensive program to increase access to affordable quality medicines.  Whether the actual structure of AMFm continues past this year or not, we need to take the lessons and apply them in guaranteeing that those in need receive appropriate and affordable malaria medicines at the closest point of care.
[1] Technical Design for the Affordable Medicines Facility-malaria. November 2007. Prepared with guidance from the AMFm Task Force of the Roll Back Malaria Partnership. http://rbm.who.int

[2] Yamey G, Schäferhoff M & Montagu D. Piloting the Affordable Medicines Facility-malaria: what will success look like? Bull World Health Organ 2012;90:452–460.

[3] Expert Advisory Group on the Affordable Medicines Facility-malaria (AMFm) Review of the AMFm Phase 1 Independent Evaluation Preliminary Report Friday 22 June 2012, Geneva

The recent scare concerning the magnitude of fake and poor quality malaria drugs in circulation has raised a number of questions about malaria drug supply management in endemic countries.  The big question is who makes the decisions about what comes in and how it is used? Debates around public and private sector medicine use further complicates the debate.

In all cases there do seem to be national malaria treatment policies that specify the types of medicines appropriate for a ‘normal’ case of malaria, a case of severe malaria and cases of malaria in pregnancy.  Within these policies are strong preferences for artenmisinin-based combination therapy (ACT) drugs. WHO has gone to the extent of examining malaria drug production and has published and regularly updated lists of ‘pre-qualified’ medicines from reliable pharmaceutical companies.  This list usually guides the recommendations and purchases of major donors like the Global Fund and the US President’s Malaria Initiative.

Even with these various safeguards, the situation on the ground – and in the medicine shops and pharmacies – is quite variable. Lets look at two extremes.

Nigeria’s national case management guidelines do specify ACTs for first line malaria treatment.  The main recommendation for treatment in uncomplicated cases is artemether-lumafantrine (AL) and as an alternative artesunate-amodiaquine (AA).  Brand names are not specified, but for government and donor programs the choices do come from the WHO pre-qualified list.

Estimates vary, but roughly half of Nigerians get their malaria treatment in the private sector.  There one still finds chloroquine and sulfadoxine-pyrimethamine products on sale.  Over 100 different ACTs are registered with the National Agency for Food and Drug Administration and Control. It is not clear whether it has been possible to test the efficacy of all these different products. Let the consumer beware.

In Rwanda, not only does the Ministry of Health set malaria drug policy, it actually enforces it.  Even in private pharmacies one can only buy the approved form of AL, Coartem.

Aside from the size of the two countries, what makes the difference? Political will to adhere to scientific evidence!

Closer to Rwanda, Edward Ojulu looks north and observes that, “Just across in neighboring Uganda, authorities say they suspect nearly 30% of the drugs imported into the country to be fake counterfeits. The tragedy is that the National Drug Authority, a Uganda Government agency that regulates manufacture, import and distribution of human drugs in the country, says it has neither the equipment nor the manpower to stop fake drugs from being sold to the people.”

Edward gets to the heart of the matter when he notes that, “Malaria is big business for pharmaceutical companies world-wide and counterfeiters also know this.” It takes a lot of political will to stand in the way of the profit motive. But that may be what is necessary to save the malaria drug supply and save lives.

Reporting from Nairobi, Inter Press Service (IPS) documents the experience of James Odhiambo who “goes from one pharmacy to the next in search of anti-malarial drugs marked with the Global Fund’s logo of a green leaf. He is looking for this specific brand because he understands that it is more than ten times cheaper than the same drug produced by different manufacturers.” James finds what he needs at the sixth shop.

Without subsidy from the Affordable Medicines Facility malaria (AMFm), these drugs would cost about $5 or two days salary. See the much sought after medicine packet in a photo on the right by Isaiah Esipisu of IPS.

IPS, on further investigation, attributed the scarcity of the subsidized malaria medicines to the low profit margin that pharmacies who agree to sell the medicines are officially allowed. While the actual price of the AMFm drugs should be $0.50 for adult and $0.12 for child doses, IPS learned form a science reporter of the Nation Media Group that, “Two months ago, we requested our reporters from different parts of the country, including rural areas, to check on retailing prices of the subsidised anti-malarial drugs. As a result, we discovered that pharmacists sold them at varying prices ranging from 80 KES (one dollar), to 240 KES (three dollars).”

IPS learned from a private pharmacist that if she sold the commercial variety of Coartem (the approved artemether-lumefantrine combination drug) she could make $2 profit. The AMFm drugs were permitted only about $0.15 profit. For this pharmacist, ” it would not make any economic … considering her costs of transporting it from the distributors, and other inputs.”

Apparently the Ministry of Health believes the problem can be solved through an “awareness campaign (that) will help consumers make an informed choice and enable them to seek outlets that sell the drugs at the right price.” The cost of transport around town seeking the correctly priced drugs may wind up to be more that the price of the drugs themselves.

AMFm is still a new program. The Global Fund explains that, “Following the Global Fund Board’s decisions on successful applications to Phase 1 in November 2009, grant amendments or new grant agreements have been signed with most AMFm Phase 1 countries and implementation has started in several countries. The first co-paid ACTs were delivered to Ghana and Kenya in August 2010.” Seven other pilot projects are in varying stages of implementation.

Nigeria started implementation of AMFm in March 2011. The Director of the National Malaria Control Program in Abuja hoped that the AMFm subsidies would help crowd out fake and substandard malaria drugs from the market by offering medicines at around $0.50 instead of the $6-8 prices per packet in shops.  Ironically conversations with people responsible for a pre-pilot of sorts carried out under a previous GFATM grant in Nigeria identified similar attitudes about profitability by medicine shop keepers. Might Nigeria be heading down the same road as Kenya?

Word is still out on AFFm implementation in Ghana. So far the Ghana Health Service is touting the benefits of AMFm – the low costs, the savings to the national insurance scheme and the edging out of poor quality drugs from the market. Interestingly, none of the news emanating from implementing countries appear to address the need for proper diagnostics to reduce inappropriate use of the malaria medicines.

Fortunately the Global Fund is planning an evaluation of the AMFm experience. This will address availability, affordability, use and market share.  AMFm is a grand experiment. We hope it is well enough designed from the start to test real life forces in the private sector. Arbitrarily suggesting profit margin is not the way to go, but in the end shop keepers and pharmacists will hold the day through their choice to participate and the prices they set.  Whether these decisions will improve coverage with appropriate malaria medicines will eventually be known when this two-year pilot finishes. In the meantime it appears that some important operational lessons can and should be learned and applied NOW.

PS – see article on low malaria transmission risk in Nairobi in Malaria Journal.

Recently in a small provisions shop in Abuja I bought a box of ‘Anti Malarial Tea’ bags. The 20 bags/sachets weighed 2 grams each. The instructions were to use “3 times daily, one bag each time.” The only ingredient listed was “Herba artemisiae annuae.”

Indications for the use of this dried herb product were as follows: “The Product can be used to eliminate plasmodium agamous body. It can also be used to control symptom and kill plasmodium. It has similar effect on resist virulent chloroquine malarias.”

The manufacturing date was blank, but the espiry date was listed as ‘2014.’ Storage was recommended as “Store in shade, light-avoided and airproofed.” In fact the tea bags were sealed in a silver colored bag.

This product was obviously not moving fast, and there was little likelihood that it was competing with orthodox antimalarial drugs. Still one might be concerned about monotherapy and drug resistance.

A recent article in the journal Molecules did address the potency of artemisia annua in different forms of extraction. The researchers found that …

… the ancient Chinese methods that involved either soaking, (followed by wringing) or pounding, (followed by squeezing) the fresh herb are more effective in producing artemisinin-rich extracts than the usual current method of preparing herbal teas from the dried herb. The concentrations of artemisinin in the extracts was up to 20-fold higher than that in a herbal tea prepared from the dried herb, but the amount of total artemisinin extracted by the Chinese methods was much less than that removed in the herbal tea. While both extracts exhibited potent in vitro activities against Plasmodium falciparum, only the pounded juice contained sufficient artemisinin to suppress parasitaemia in P. berghei infected mice.

Here again one wonders if using the dried herb as tea would contribute to parasite resistance.  Another group of researchers tested the tea on malaria in mice and found that, “The tea does not decrease the parasitaemia fast enough.”

Herbal medicines form the base for many remedies throughout the world. Although a website for the actual company named on the box, Xiamen Jianxi Health Product Co., Ltd., was not found, another site listed 70 different teas including –

• Eye Bright Tea
• Kidney & Liver Mind/Care/Flush Tea
• Anti-Hypertensive Tea
• Anti Malarial Tea
• Refreshment & Heat Clearing Tea
• Cough Sputum Removing Tea
• Stomach & Heart Burn Relieving Tea

In our quest for universal access to and appropriate use of ACTs, we forget that people still have many treatment alternatives.  Until we can make quality ACTs cheaply and easily available in endemic countries, people who suspect they have malaria will make all efforts – whether teas, antibiotics, analgesics, inefficacious malaria drugs and the like – to address their problems.

The burden of malaria is made worse when medicines consumed to treat the disease are either fake/counterfeit or substandard. This may result from intentional and illegal processes or as a result of poor shipping and storage procedures that reduce efficacy or allow expiration. Over 15% of drugs sold may be fakes.

Two recent initiatives hope to prevent the consumption of counterfeit malaria drugs.  JustMeans.com reports on a way to empower consumers in detecting fakes in Ghana and Nigeria. “Ghanaian social enterprise MPedigree and Hewlett Packard have launched a lifesaving service that will combat counterfeit pharmaceuticals by enabling people in Ghana and Nigeria to verify the authenticity of their malaria medication via text message.”

A scratch-off code found on the medicine packaging can be texted to a free number to verify the drug’s authenticity. Local pharmaceutical companies are actively involved in the process.

A second approach is being made possible through pilot activities of the Affordable Medicines Facility for malaria (AMFm), which is being managed by the Global Fund. AMFm intends to make appropriate approved malaria medicines available in public and private settings at prices comparable to the old first-line drugs, chloroquine and sulphadoxine-pyrimethamine. This will hopefully drive unapproved and potentially fake medicines from the market.

In Nigeria, “the official take off of the (AMFm) project in January … appears set to halt malaria related deaths from its communities by making available high quality, affordable and effective Artemisinine-based Combination Therapy (ACT) through the public, private, non-profit and for-profit organizations to all its citizens.” ACTs, which are normally quite expensive, will become more accessible.

As malaria elimination efforts become more effective. Timely surveillance and treatment will become even more important. Other tools like the use of minilabs can help. All efforts must be focused on maintaining the quality of our malaria drug supplies in order to reduce morbidity and achieve the Millennium Development Goals.

According to the World Health Organization, its “Prequalification Programme aims to make quality priority medicines available for the benefit of those in need.” The results is a “list of prequalified medicinal products used for HIV/AIDS, malaria, tuberculosis and for reproductive health.” The list is supposed to guide purchasing decisions of all UN and development partner agencies.

The Global Fund is one of the international agencies that encourages its recipient countries to buy from the prequalified list, and through the Affordable Medicines Facility, malaria (AMFm) intends that not only good quality is promoted, but reduced prices. Interestingly, this development has raised concern in Nigeria, the biggest market for malaria drugs in Africa.  As Soyombo Opeyemi explains in the Daily Independent …

The proposed intervention by The Global Fund to drastically reduce prices of Artemisinin Combined Therapies (ACTs) through its Affordable Medicines for Malaria programme (AMFm), which will see ACTs from six foreign companies sell from September 2010 at a monitored price regime of between N60 and N70 a dose [between US $ 0.40-0.47], as against the current average price of N350 for most ACTs produced or marketed in Nigeria, has generated a rumpus in the last few weeks in the media.

The controversy arises over two competing development goals – making high quality medicines available to those in need at affordable prices vs strengthening local industrial capacity. As seen in the Table below, many of the manufacturing sites are in ‘developing’ countries, but as Abdullahi Mohammed points out in This Day …

(These manufacturers) also have access to cheap credit, enjoy tax reliefs and export incentives, among other forms of official assistance. All this makes it difficult for Nigerian manufacturers, who currently have practically no access to bank credit and are stuck with providing their own infrastructural requirements, to compete with their foreign counterparts.

The Nigerian malaria drug market is vast. There are dozens of Arthemeter-Lumefantine ACTs approved for sale and over 100 Artesunate-Amodiaquine formulations. Some of these are produced by actual Nigerian manufacturers while others are imported by a Nigerian Company from India and elsewhere. It would be important to identify the actual indigenous manufacturers who are losing out to the six big international pharmaceutical producers.

It is not clear whether there are actual foreign assistance efforts aimed at building the capacity of malaria endemic countries in Africa to produce their own pharmaceutical products.  If such a longer term project were started in parallel with efforts like AMFm, there may be more acceptance for temporary set backs in the local market, knowing that in good faith, the international community is trying to strengthen countries’ abilities to fight malaria into the future.

the challenge though is which aid program can address the infrastructural problems facing Nigerian manufacturers – lack of reliable electricity, water supply and roads – as well as a legal framework that protects intellectual property and gives the local companies a fair chance to compete.

Yesterday we presented some of the findings from the malaria drug studies conducted by US Pharmacopeia (USP) in Madagascar, Uganda and Senegal.  We conjectured that the problem may be less in the public sector since it is often guided by WHO drug pre-qualification approvals – especially if the drugs are purchased through major donor programs like Global Fund, World Bank or PMI. At times the US Food and Drug Administration may be involved.

After reviewing the whole report from USP our faith in the public sector is somewhat shaken.  While the chart at the right shows that the informal and private sectors have the greatest proportion of substandard malaria drugs, the public sector is not without problems – 23% of SP products tested 14% of ACTs in the public sector were not up to standard.

An interesting finding is that the problem of substandard drugs rests in inadequate amounts of active ingredients or the presence of impurities in the product – not specifically the issue of counterfeit/fake medications.

Problems in the public sector may arise in the procurement processes. In some cases there are central procurement agencies in the national health ministry. In some countries states/provinces and local governments/districts can do their own tendering and procurement. This opens the door to a variety of medications entering the public sector, not just the few recommended prequalified products.

As mentioned in yesterday’s post, it is often necessary to back to the manufacturer to correct problems.  The USP report had the following observations about common brands that may find their way into public procurement processes:

The results were similar for the ACT products, that is, samples of most of the brands either all passed or all failed the QC test requirements, with only a few exceptions. One example is the Larimal brand, sampled from both Uganda and Senegal. All six Larimal samples tested failed the QC test requirements. Coartem and Duo-Cotecxin brands, on the other hand, were found in all three countries, and all samples of these brands passed the testing requirements. Also, all samples of the Lonart brand sampled from Uganda passed the QC test requirements.

This type of information should inform both donors and national malaria control programs. We look forward to reports from the seven other countries in the study.

While research for new malaria drugs continues, supplies of existing drugs are threatened by poor quality, parasite resistance and counterfeiting.

With USAID support, US Pharmacopeia (USP) has been studying malaria drug supplies in 10 Sub0Saharan Africa countries, and has recently issued a press release on its findings in three locations. USP found that, “a high percentage of medicines circulating on national markets are of substandard quality and thus may contribute to the growth of drug-resistant strains of Plasmodium falciparum, the most virulent form of malaria.”

Reports on the first three countries, Madagascar, Senegal and Uganda, looked at the recommended first line case management drugs, artemisinin-based combination therapy (ACT), and sulfadoxine-pyrimethamine (SP), which is used to prevent malaria in pregnancy. Between 26% and 44% of the drugs that were tested were sub-standard, that is they …

• do not contain the correct amount of the active ingredient(s)
• do not dissolve properly in the body or
• include unacceptable levels of potentially harmful impurities.

While USP called on local drug regulatory authorities to step up to the challenge of testing and enforcement, but also recognized that the problem traces back to the manufacturer. “The results also showed that, as a general rule, when a brand passed or failed in one country, it would also pass or fail in other countries. This indicates that the problem of quality is created at the source, rather than during passage through the distribution chain.”

Other countries included in USP the study are Cameroon, Ethiopia, Ghana, Kenya, Malawi, Nigeria and Tanzania. In a smaller scale study two years ago, Roger Bate and colleagues reported similar poor quality in 35% of malaria drugs sampled in 6 countries, five of which overlap with the USP work.

Last July VOA reported that fake pharmaceuticals are a bigger threat to West Africa than drug trafficking. At that time “The UN estimate(d) that more than half of anti-malaria medication available in West Africa is of sub-standard quality.”  A seminal study on drug quality in Nigeria in The Lancet supports the USP’s conclusions that the problem often lies at the source – “the main reason for such products not complying with pharmacopoeial limits is poor quality control and quality assurance during manufacture.”

We hope that the malaria medicines used by national control programs and purchased with WHO’s pre-qualification recommendations in mind, are safe, but the private market for antimalarials is wide. It may be unreasonable to expect that each country’s drug regulatory authority take full responsibility for guaranteeing drug quality when we could go to the source – the manufacturers, or at least the importers – and prevent the problem from even entering endemic countries.

Is the international community living up to its responsibilities to protect the quality of malaria drugs and thus save lives?

The old saying goes, ‘don’t look a gift horse in the mouth.’ Equine experts can tell a lot about the age, health and travails of a horse by examining the teeth and mouth.  The admonition not to examine an animal that is a gift might arise from not wanting to embarrass the giver, and why worry anyway if you did not pay for the horse.

It may me another matter when the intended gift is to be swallowed.

News reports record that, “The Chinese government on Monday (18 January 2010) donated over 244,000 doses of anti-malarial drugs to the Uganda in a bid to fight the deadly disease that kills over 320 people daily in the East African country.” The donation includes 144,000 doses of Arco and 100,000 doses of Duo-Cotexin.

Supplies of the same two drugs were also donated by China in April 2009. The two medicines apparently are not yet included in the country’s essential medicine list or listed as firstline treatments in the national malaria strategy/policy. “The drugs are, however, still awaiting pre-qualification from the World Health Organisation (WHO).”

Duo-Cotexin is a dihydroartemisinin plus piperaquine product (of which other brands include Artekin, Artecom, CV8) and is “given in a four-dose regimen that has proved highly effective and well tolerated in South East Asian trials.” ARCO is a combination of two drugs – Artemisin and Naphthoquine Phosphate. At present the only two combinations that have WHO pre-qualified products are Artemether+Lumefantrine (AL) and Amodiaquine+Artesunate (AA).  AL is the firstline treatment used in Uganda.

The two donated drugs apparently do offer a more convenient regimen than AL, which is taken for 3 days. “For Arco, its dose is swallowed once while Duo-Cotexin the tablets are swallowed once a day as prescribed by a doctor.”

The main concern is that when there are many different types of drugs on the shelves with different regimens, as is the case here, health workers and patients can get confused. There may also be different formulations for different age groups.

Granted, Uganda has not often had the luxury of too many malaria drugs, and shortages have been common. Thus, there may be the tendency not to look this gift horse (or medicine) in the mouth. Uganda, like most endemic countries, is definitely under pressure to scale up for impact this year.

We can only encourage the malaria partners in Uganda to practice pharmaco-vigilance with these donations and ensure thorough in-service education for health staff and patient education to promote adherence among clients.