Tropical Health Matters

The Wall Street Journal quotes Novartis Chief Executive Daniel L. Vasella as saying, “In the end the only drug that matters is the drug that is swallowed.” The article goes on to explain how Novartis has developed a form of Coartem that is “Dispersible, that is small, cherry-flavored and dissolves easily,” as a way to ensure that the dispensed medicine is actually swallowed. The article also addresses other flavors that may be tried.

Much progress has been made in packaging malaria drugs for different age groups, especially children, when before there were only standard adult doses than had to be divided – a challenging task for many parents. The alternatives for children were more expensive syrups that were not always stable in tropical climates.

The article also addresses other challenges to ensuring children get their drugs. “But efficient channels to distribute the products are rare, giving rise to what health workers call ‘pile-up’ of drugs trying to reach villages and health clinics.” Efficient distribution is essential since artemisinin based medications have a relatively short shelf life and can expire within 18 months of arriving in a country.

Another challenge is cost. Medicines bought through Global Fund Grants are generally made available free for children in public or NGO clinics. Pilot programs are underway to see how subsidized price antimalarials can be made available through the private sector which may actually account for 50% or more of actual malaria treatments provided.

Three challenges that are not mentioned in the article include –

• For one, when drugs are made available for free or at reduced cost only for children, there will be leakage into wider use as health workers or medicine shop keepers will provide multiple packets of the child drugs to satisfy their adult clients/customers.
• A second unmentioned challenge is the tendency to overprescribe malaria drugs, especially among adults.  The answer to this is case management that includes diagnosis using a laboratory, but more likely rapid diagnostic tests, which can be used at the primary care level
• Finally there is the issue of compliance.  Artemisinin-based combination therapy generally is taken twice a day for three days. If medicine providers do not counsel clients on the need for full compliance children may swallow only a few doses and not only fail to be cured but also contribute to drug resistance.

Malaria case management is a complicated process that begins with the drug manufacturer and ends in the home. All partners along the way must be vigilent if children’s lives are to be saved.

The introduction of Artesunate-Amodiaquine in M’lomp village, Senegal has been monitored over time by Sarrassat and colleagues.Their efforts were motivated by experiences in Thailand, South Africa and Zanzibar, where a decrease in malaria morbidity was observed following the introduction of artemisinin-based combination therapy (ACT).

Decreased incidence has been postulated as an effect of artemisinin-based medicines’ ability to kill gametocytes and reduce transmission (Drakeley et al.; Nosten et al.; Carrara et al.; Barnes et al.; Battarai et al.).

Sarrassat’s team also observed a decrease in the incidence rate and repetitiveness between 2001 and 2002. They were worried that lower rainfall might also have contributed to the findings, especially since treatment coverage was less than ideal.

Ultimately Sarrassat et al. concluded that, “In sub-Saharan countries, in order to optimize the impact on malaria morbidity, ACT deployment must be supported, on the one hand, by a strengthening of public health system to ensure a high ACT coverage and, on the other hand, by others measures, such vector control measures.”

A home management strategy has been one recommendation to improve the ability of health systems to increase ACT coverage. Generally though timely procurement and supply procedures are required to make ACTs available for the whole population at risk. In order to do this, health systems need strengthing as Sarrassat suggests.

The Clinton Foundation is tackling a challenge that faces the world market for artemisinin-based combination therapy (ACT) medicines – the supply, demand and ultimately the price of the basic ingredient. The move by malaria control partners to get countries to switch to ACTS and save lives amid the failing efficacy of chloroquine and sulfadozine-pyrimethamine was relative swift and did not account for the normal market forces involved in introducing new pharmaceutical products, especially when these are provided free or at cost to the end user.

In addressing Kenya’s rapid policy change to ACTs, Zurovac and colleagues concluded that, “Changes in clinical practices at the point of care might take longer than anticipated. Delivery of successful interventions and their scaling up to increase coverage are important during this process; however, this should be accompanied by rigorous research evaluations, corrective actions on existing interventions and testing cost-effectiveness of novel interventions capable of improving and maintaining health worker performance and health systems to deliver artemisinin-based combination therapy in Africa.” They also said that policy makers should be “carefully prepared for a myriad of financial, political and legislative issues that might limit the rapid translation of drug policy change into action.”

According to news reports, “In 2002, Clinton established an HIV/AIDS initiative that sought to negotiate lower prices for anti-retroviral treatments, and he since has expanded his focus to include malaria treatments such as artemisinin-based combination therapies, or ACTs. One of the factors making the price of artemisinin so volatile – fluctuating from $155 to $1,100 per kilogram in recent years – has been a wildly erratic cycle of shortage and excess of the extract.”

Earlier this year, one of the major producers of ACTs, Novartis, announced, “a 20% average reduction in the price of Coartem^® tablets (artemether/lumefantrine 20 mg/120 mg), the state-of-the-art artemisinin-based combination treatment (ACT) for malaria. Starting this Friday, which is World Malaria Day, this price reduction will increase access to Coartem for millions of malaria patients, especially children in low income regions of Africa.”

Of course Novartis, like other producers must not only rely on supplies of this natural product which is subject to the normal risks of agricultural production, but also to the fact that countries who need ACTs do not always order their supplies in a timely and coordinated manner. This is despite the fact that Novartis has had an edge on other ACT manufacturers by being the first WHO prequalified drug, guaranteeing its priority purchase through Global Fund grants.

The AP story goes on to explain that, “Clinton said he has negotiated with six suppliers involved in producing ACTs that have agreed to certain price ceilings that the foundation says will help keep prices constant and not so dependent on the fluctuating cycles.The agreements are with two suppliers at three levels of the supply chain — raw material, processing and final formulation — and the foundation hopes to add more suppliers.”

Previously we have addressed the potential for synthetic artemisinin production as well as the need for continued research into new and alternative malaria drugs. Stabilizing the price of the raw product will certainly have short term benefits. The long term requires increasing the scope of our malaria treatment arsenal.

The process that ensures people in malaria endemic countries get appropriate and timely life saving treatment starts far away from the individual sufferers. Researchers determine safe and efficacious medicines, international agencies issue guidance, national governments develop treatment policies, guidelines and standards, pharmaceutical companies scale up production, funds to purchase drugs are mobilized, orders for medicines are placed and shipped … and after all these steps treatment has still not reached those in need.

Once the medicines are in the country (either produced there or imported) the supply/distribution chain continues through both public and private warehouses and medical stores. In the public sector the debate over who delivers or collects the medicines start – do states, regions, and districts collect from the national stores or are the medical stores responsible for shipping supplies out to the regions and districts. The debate begins again at the district level when individual facilities contemplate how to get their own supplies.

Assuming the appropriate medicines reach the shelves of the frontline clinic or medicine shop, the next step is for clients to obtain these for themselves and their children.  Eligibilty questions come up – are free medicines only for children or everyone.  Finally the medicines reach the home.  Success of malaria control ultimately rests on the last step, taking the full, correct dose of the medicines.  So what do we know about adherence to malaria drug regimes?

In Senegal Souares and colleagues looked at adherence to a regimen of SP-amodiaquine, in use then, as a proxy for adherence to ACTs at the point when this would be introduced, since both had a 3-day regimen. They found that, “35.3% of children did not comply with the recommended doses and 62.3% did not exactly adhere to the drug schedule. Despite the good efficacy of the drugs, adherence to the therapeutic scheme was poor.” Even though efficacy was good, they foresaw a time when poor adherence could lead to drug resistance and recommended training of health workers to improve patient-provider communication about adherence.

We cannot wait for haphazard adherence to lead to ACT failure. ACT performance standards are needed and should be part of the roll out of any government or donor funded malaria treatment program.  Importantly, training on these standards must reach the private and informal sector, too.

Private sector partnership in malaria control does not mean that drugs, nets and other malaria commodities provided by donors for national control programs should disappear from the public sector and find their way into shops and market stalls. Unfortunately this is what has been reported in Cameroon.

The Post of Buea reported Friday that, “Corruption has been identified as the main jinx hindering the effective distribution of modern malaria drugs, subsidised by the Global Health Fund for Malaria AIDS and Tuberculosis. The Permanent Secretary at the National Malaria Control Programme, Dr. Raphael Okalla, made this revelation during a press conference in Yaounde February 14. He said corrupt doctors in some government hospitals were pilfering the subsidised drugs and giving them out to people to sell at higher prices for them to make gains.”

Pilferage is an issue that is often addressed in guidelines, such as ones on ACT from Zambia wherein there is mention that, “A key issue to be addressed is the prevention of pilferage from the public to the private sector facilities.” UNICEF offers advice that looks back near the start of the supply chain, “To avoid pilferage, port storage, container demurrage etc., it is important that shipments are cleared and removed from point of entry (ports/airports as quickly as possible.” WHO Afro recommends proper storage facilities and forecasting of needs as steps to prevent pilferage.

While the problem is often discussed, documentation can be problematic. The Chronical of Lilongwe reported on general pilferage in 2004. “A clinician, who refused to be identified, informed us that the hospital received a lot of drugs but the problem was that most of them disappeared to private clinics which several individuals working at the hospital have opened. ‘For many months now,’ our informant began, ‘the hospital lacks a whole range of antibiotics such as Ciprofaxine, Augmentin or Amoxilin. We may have some of them for one month and then they vanish for another six months. Can you imagine that?'” Those interviewed at the hospital said the problem stems in part from poor documentation and supervision.

In The Daily Champion of 11 December 2007, Nigeria, “Dr. Dora Akunyili, painted a sad picture of how common criminals, petty thieves and child murderers masquerading as pharmacists, patent medicine store operators and government functionaries have been colluding to deprive children and nursing mothers of life-saving high dose Vitamin A capsules, Mectizan and Coartem tablets, Oral Rehydration Salts (ORS), cold chain equipment and other essential supplies.” Again, specifics on the location and extent of these transgressions is minimal.

One of the benefits of performance based funding by the Global Fund may be to institute accountability measures that could reduce leakage and pilferage. The Fund notes that with, “transparently by performance-based funding processes, grants are reaching overall programmatic targets.” The will to monitor, supervise and guarantee accountability needs to be extended to all aspects of malaria programming no matter which donor provides the funds.

Despite a call for pharmacovigilence by the Kenya Pharmacy Board, fake duo-cotexin and cotexin were found in Kenya recently. The producers of duo-cotexin [40mg of dihydroartemisinin (DHA) and 320mg of piperaquine (PPQ)] have promised to introduce counterfeit-proof packaging with features such as a hologram, but in the meantime in Kenya, let the buyer beware. As a Daily Nation editorial opines, at present, “The average person is hardly in a position to differentiate between the counterfeit and the genuine drug. This would mean that there are people who are unnecessarily losing their lives.”

The Daily Nation pinpoints the problem within the Pharmacy Board. “Although the Pharmacy and Poisons Board has drug inspectors who are tasked to not only combat counterfeit drugs but also to ensure that drugs in the market are duly registered, it would appear that they are ill-equipped to police the drug market,” even though the Board claims that, “We ensure that all drugs, locally manufactured, imported and/or exported and registered to ensure their safety quality and efficacy” (sic).

With the presence of major donor programs such as the Global Fund and the President’s Malaria Initiative, Kenya may feel that much of its malaria drug need is being met with provisions of the only WHO prequalified arteseminin-based combination therapy antimalarial, Coartem, but that does not account for the private sector where the fake duo-cotexin appeared. Donor support is needed, not only to import more Coartem, but also to improve the capacity of the National Pharmacy Board and National Quality Control Laboratory to ensure that all Kenyans have access to safe and effective malaria medicines, whether they use the public or private sectors. This same need holds true for other countries in the region.

Front line clinics in Kenya, such as the one pictured here, carry four different dosage packs of Coartem to cover all age groups. In addition, coartem is given for free to all patients, and people over five years of age are generally tested before this artesunate-based combination therapy (ACT) drug is prescribed. This comprehensive approach means that there is no discrimination in providing care.

In other countries free ACTs that have been provided through donor support are intended only for children less than five years of age. ACTs for the remainder of the population have not been bought by health authorities based on concerns for cost. Sometimes then, the free ACTs from donor programs have been used inappropriately for older patients. Kenya appears to be avoiding this problem.

The lesson is even larger than that of the need for drug forecasting and adequate procurement. The Kenyan Ministry of Health recognizes that ACT has a preventive effect as reported by Sutherland and colleagues whose “results suggest that co-artemether has specific activity against immature sequestered gametocytes, and has the capacity to minimize transmission of drug-resistant parasites,” though this can be modest in some settings. If only a portion of the population is treated, this benefit of reducing transmission is missed.

Another benefit is economic. The Kenyan Ministry of Health also recognizes that if a parent is sick with malaria and misses work, the whole family will be affected. Just as WHO is calling for free nets for all, there also needs to be free ACTs for all who are infected with malaria. To do this we need continued donor and country support as well as a wider range of WHO pre-qualified ACTs to create competition and bring ACT prices down.

Uganda was the darling of hte international public health community some 15-20 years ago when it tackled the HIV/AIDS epidemic head on with local initiative, both by government and civil society. Today in the era of huge disease control grants Uganda is not doing so well. In August 2005 problems within the Project Management Unit within the Ministry of Health that oversaw all Global Fund grants implementation led to a suspension of all grants. This was a major set back for the Round 2 Malaria Grant, which had started in March 2004. The suspension led to serious drug shortages for the three disease programs.

Although a recently published progress report at the Global Fund shows that grants where government agencies are the principal recipient perform more poorly than those managed by NGOs, the Uganda experience was an extreme event. It appears that the country may not have fully recovered from the problems.

A headline in the Monitor newspaper of 11th July 2007 read, “Shs3.7 Billion Malaria, ARV Drugs Rot in National Medical Stores” (about $US 2.3 million). According to the article, a team of MPs “were shocked to find eight containers of 2-feet, full of expired drugs yet Ugandans are perishing in hospitals without treatment.” These included both ARVs and antimalarial drugs. It was reported that most of these drugs did not ‘belong’ to the National Medical Stores (NMS) but to donor programs. This may point to a deeper problem: the NMS should be part of the management process for these donor programs, not just a passive depository for supplies.

The General Manager of the NMS complained that, “Many of the programmes procure short-lived drugs and leave them for a long time at NMS, which in many cases expire.” The reality is that the current first line antimalarial drugs, artemisinin-based combination therapies (ACTs), have a short shelf life. As seen in the attached picture of a packet of antesunate-amodiaquine, ACTs typically expire two years from manufacture. This means that national malaria programs must forecast, procure and manage ACTs in such a way as to guarantee prompt use of supplies.

This news speaks poorly for the malaria grants in Uganda. The Global Fund publishes report cards and score cards on all grants, and one can easily find these on each country’s page at the Global Fund Website. The most recent progress report for Uganda’s Round 2 malaria grant is November 2006. That progress report noted that, “Performance has been poor because of the loss of momentum due to the suspension of GF grants in Uganda for a period 2.5 months, as well as the disbandment of the Project Management Unit (PMU)” and that implementation was behind schedule.

Concerning procurement, the report stated that, “On lifting the suspension, an aide memoir was signed at which certain actions were agreed upon to be achieved by the PR and CCM. This included the recruitment of a Third Party procurement agent and the revision of work plans and procurement plans to take account of the delays due to the suspension. To date, a procurement agent has not been appointed.”

More specifically, the New Vision newspaper of 11 March 2007 reported that, “The Global Fund has permanently terminated two grants to Uganda for malaria and tuberculosis because of what it called “unsatisfactory performance.” As a result, Uganda has missed about $16 million,” of which $14.7 million was for malaria. The Round 4 malaria grant, which started in December 2005, after the problems of suspension had been resolved, remains. There is hope, as the most recent progress report for this grant, issued in January 2007, indicates that WHO is helping address procurement problems. The report states that, “This grant is achieving its targets, with the first tranche of ACTs having been purchased by WHO. Despite the setback of GF grants in Uganda due to the suspension, this grant, which is largely procurement-dependent, is moving ahead with the support of WHO.”

While we cannot change the shelf life of ACTs, we can improve procurement and supply management of malaria drugs. Although the Global Fund has canceled few grants, it is not unwilling to take action. Ideally RBM partners should step up and provide technical assistance to help grant performance long before the grant cancellation question arises.

One of our newest African malaria advocates, the Voices Mali Coordinator, Djiba Kane Diallo, appeared in a press conference on French TV channel TV5.  Djiba was in Paris at a press conference about the lack of progress toward achieving the Millennium Development Goals for health.  The conference was organized by Médecins du Monde and the story was broadcast globally on TV5.  She was interviewed and spoke specifically about logistical problems in managing malaria commodities in Africa.  Supply chain management is one of the systems that need to be strengthened to improve malaria control across Africa.

Watch the clip (in French!) at http://www.tv5.org/TV5Site/info/jt_ja.php?edition=20070705&par=6

Les pays européens doivent investir d´urgence dans les services de santé des pays pauvres 

(aired on 5 July 2007)

For non-Francophones, here is the translation of the newsclip:

In a meeting in Paris on July 5, 2007, European NGOs demand that European governments invest more in health services in developing countries in order to meet MDG goals.

It’s the first evaluation of the Millenium Development Goals. At the midway point, a report edited by 15 NGOs gives a poor grade to Europe, and to France in particular. Current financing for goals like reducing child mortality means that they will be met only in 2220. Twenty million Euros were promised for health, but only half of what was promised has been spent.

[Patrick Bertrand, NGO network leader] “Data from 2004-2005 shows that France gives 4% of its foreign aid for the health sector. The average among OECD countries is 11%.” 

On the ground, they are impatient for the missing funds. For the NGO Voix du Mali, which works to control malaria, it’s an emergency. Medicines are there, but there are few funds to distribute them.

[Djiba Kane Diallo, Voix du Mali] “If there is more financing, that enables countries to not only to distribute the medicines out to the community level, but also to stock them in appropriate conditions.”

In the report they highlight not only the need for more money, but also the need to change practices and policies in the health sector. Promote research, train health personnel, and put more responsibility on African governments.

[Michele Brugiere, Medicins du Monde] “African governments need to commit more of their budgets to health - they should be comitting 15-20%. Right now it’s two, three, four percent.”

MDG health goals can still be reached, but donors’ political will must now change into economic reality.