Strengthening Supply Chain Security For Essential Antimalarial Drugs

Secure and reliable supply chains for life-saving medicines are essential features of the global health landscape. They ensure that quality approved drugs are manufactured and available in the quantities needed, without interruption. For the fight against malaria, securing supply chains for quality, life-saving antimalarials involves the collective effort of a range of organisations working to mitigate the risk of any shortage of these drugs. A recent success in this area has been the quality approval of a second supplier of injectable artesunate, the drug recommended by the World Health Organization to treat severe malaria.

A health worker prepares an artesunate injection.

The organisations that work in concert to secure supply chains for life-saving antimalarial drugs include the WHO, product development partnerships (PDPs) such as Medicines for Malaria Venture (MMV), and large donors including the US President’s Malaria Initiative (PMI) and the Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund). These organisations work closely with pharmaceutical companies with the interest and capacity to manufacture antimalarial drugs, as well as with national health systems that introduce and deliver these drugs to patients.

As a PDP, MMV plays a unique role in bringing together philanthropic funders, the pharmaceutical industry and academic research institutions to undertake research and development (R&D) for antimalarial drugs, which “they would normally be unable or unwilling to pursue independently, without additional incentives.”

Through the collective efforts of these organisations, and with direct support from MMV, a highly effective drug to treat severe malaria, injectable artesunate, was introduced into the world market. In 2010, Fosun Pharma became the first manufacturer to become quality approved by the WHO to supply injectable artesunate on a large scale for global procurement and distribution.

Since then, Fosun, the sole supplier of the drug at the time, had supplied over 127 million vials of injectable artesunate to malaria-endemic countries, saving an estimated 800,000 more lives than would have been possible without the drug, according to an MMV analysis of research findings on the drug.

In December 2018, a second manufacturer, Ipca Laboratories, also became quality approved by the WHO to supply injectable artesunate, which was considered a major milestone in securing the supply chain for this essential life-saving treatment. It was the result of four years of work on the part of MMV and partners to support Ipca to achieve the WHO’s high quality standards for the drug.

Securing this second manufacturer for injectable artesunate ensures that any unforeseen or catastrophic event from any one supplier will not result in a global shortage of the drug.

“We’re lucky that in the last 8 years, there hasn’t been a major problem. But there could have so easily been,” Pierre Hugo, senior director of Access & Product Management at MMV, told Health Policy Watch. “The benefits far outweigh the costs of supporting a second manufacturer.”

“The US President’s Malaria Initiative is pleased to see a second supplier of injectable artesunate enter the market,” Kenneth Staley, US global malaria coordinator for PMI, said on these efforts. “Additional quality suppliers support a healthier marketplace for this lifesaving medicine.”

“We know that Ipca is coming along – they have a quality product for the injectable [artesunate], but they are not yet producing at scale, and this will take some time,” Martin Auton, manager of Global Sourcing: Pharmaceuticals at the Global Fund, told Health Policy Watch.

“The supply will still be tight compared with the demand for the coming year probably,” he said.

The Life-Saving Impacts of Injectable Artesunate

In a rural part of Uganda, a young child named Reagan fell sick with severe malaria. When he was brought to the health centre by his parents, he was semi-conscious and with a high fever.

“Severe malaria typically occurs due to delayed treatment of uncomplicated malaria,” and “is defined by clinical or laboratory evidence of vital organ dysfunction,” MMV’s Severe Malaria Observatory portal explains.

Reagan was in a critical state, and needed immediate treatment with a safe and effective drug. Fortunately, the health centre stocked injectable artesunate. Soon after the drug was administered, Reagan’s health improved, and within several days he was able to take a course of oral antimalarial treatment.

Without injectable artesunate, Reagan would have been given quinine, a much less effective drug. Compared to quinine, injectable artesunate offers a 22 to 35% further reduction in mortality, the research study on the drug found.

After further treatment for anaemia caused by the severe malaria, Reagan left the health centre smiling and full of life. Watch the full story of “How Reagan beat severe malaria” in an MMV video on the life-saving impacts of injectable artesunate.

Globally, around 435,000 people die from severe malaria each year, with the Africa region bearing the largest burden, having “92% of malaria cases and 93% of malaria deaths,” a WHO fact sheet explains.

“In areas with high transmission of malaria, children under 5 are particularly susceptible to infection, illness and death,” and “more than two thirds (70%) of all malaria deaths occur in this age group,” it says.

“You see the drug used on a child that’s 4 or 5 years old – a child on the brink of life and death. And then you see them the next day, and they’re able to sit up and walk around. It’s amazing to see,” Hugo of MMV said. “And it makes you proud to be involved.”

A child receiving treatment with injectable artesunate.

Global Efforts to Secure Quality-Assured Antimalarials

In 2011, Médicins Sans Frontières‎ (MSF, Doctors Without Borders) released a policy paper advocating for the switch from using injectable quinine to using injectable artesunate to treat severe malaria. “[T]he latest scientific evidence clearly shows that many more children’s lives can be saved by switching treatment from quinine to a more effective drug, artesunate,” it said.

However, it noted that “making this switch will require a concerted effort and dedicated support from the international community.”

Hugo of MMV explained that all the donors and the various organisations have put significant effort into supporting the scale-up and the introduction of injectable artesunate, and that the introduction of the second supplier, Ipca, was an important outcome of these efforts.

“Diversifying supply is crucial for any drug,” he said, “but to be able to diversify a quality approved drug is even more important.”

In order for antimalarial drugs to be procured by international donors and organisations for large-scale distribution, these drugs must first be quality assured.

The WHO is the primary global body “to ensure that diagnostics, medicines, vaccines and immunization-related equipment and devices for high burden diseases meet global standards of quality, safety and efficacy,” the WHO website explains.

The WHO does this through its prequalification process that “consists of a transparent, scientifically sound assessment, which includes dossier review, consistency testing or performance evaluation and site visits to manufacturers. This information, in conjunction with other procurement criteria, is used by UN and other procurement agencies to make purchasing decisions regarding diagnostics, medicines and/or vaccines,” it says.

WHO prequalification “enables international donors to procure the drugs. It’s the Global Fund, President’s Malaria Initiative, and UNICEF – these are the core donors that procure the majority of the drugs for malaria,” Hugo said. “Without these donors, it would be very challenging to make quality drugs available for malaria.”

According to the Global Fund’s Quality Assurance Policy for Pharmaceutical Products [pdf], “Global Fund grant funds may only be used to procure antiretrovirals, antituberculosis and anti-malarial FPPs [finished pharmaceutical products] that meet the following standards… (i) Prequalified by the WHO Prequalification Programme or authorized for use by a Stringent Drug Regulatory Authority (SRA); or (ii) Recommended for use by an Expert Review Panel (ERP).”

In lieu of WHO prequalification, the Global Fund has established the Expert Review Panel (ERP) recommendation process as a stop-gap measure to provide interim quality approval for certain pharmaceutical products, when “supply of that product is more important than waiting another 6 or 12 months until the full [WHO] approval happens,” Auton of the Global Fund explained.

The Global Fund ERP applies to pharmaceutical products already in the WHO prequalification pipeline that have passed the majority of the WHO’s quality assurance testing, and for which the outstanding risks are minimal.

MMV, the WHO, the Global Fund and other international actors in the fight against malaria each play distinct but interconnected roles in securing supply chains for the reliable procurement and distribution of essential antimalarial medicines.

“If we look at the Ipca artesunate injection… [MMV and the Global Fund] have had our separate strategies, but they are complementary,” Auton said. “We are aware of what each other is doing and we use our different tools available to pull different levers.”

MMV’s Hugo concurred: “Everything is done in collaboration with partners.”

Supply and Demand for Antimalarial Drugs

In cases where demand outstrips supply, and where life-saving drugs are at stake, diversifying supply is a crucial measure to ensure supply chain security. However, for certain pharmaceutical products, having too many suppliers could reduce the viability of manufacturing those drugs.

“More supply is not always better,” Auton said.

For some antimalarial treatments, “the volumes are fairly low, so it’s getting an optimal number of suppliers that can supply the product reliably, but not too many, because then you start diluting the volumes that make it viable,” he said.

For these types of treatments, including injectable artesunate, he said the Global Fund’s strategy has been “to have the right number of suppliers, which is typically more than one.”

Over the last three years, for “the artesunate injection and the SMC [seasonal malaria chemoprevention] medicines, there has been very tight supply and demand,” Auton said.

This is “still going on now, because we really only have one source for both really producing at volume,” he said.

While there has been a “massive scale-up [of injectable artesunate] over the last 3-4 years,” Auton explained that this is due in part to increasing demand, but also to stockpiling that is the result of overambitious roll-out plans.

Despite the recent “plateau of orders,” he said, Auton thinks “the demand is still growing.”

Administering SPAQ for SMC.

The dynamics of this demand, Hugo explained, are related to the process of rolling-out injectable artesunate at the national level. Many health systems are still in the process of transitioning from reliance on quinine to injectable artesunate to treat severe malaria.

He described a recent survey conducted by MMV in the Democratic Republic of Congo, which found that around the capital Kinshasa, only 11% of patients with severe malaria were treated with injectable artesunate. The rest, he said, were treated with quinine.

“Being able to get those core high-burden countries on board is crucial,” Hugo said, noting that scaling up the delivery of the drug depends on a range of factors, which includes funding as well as political willingness to make the transition.

He noted that regardless of the supply, “no drug is a medicine until it’s in the hands of the patient.”

MMV: Securing Supply Chains for Essential Antimalarial Drugs

As a PDP, a core aspect of MMV’s work is supporting manufacturers to obtain WHO prequalification, and to bring production of essential antimalarial drugs to scale.

In addition to securing the supply chain for injectable artesunate, MMV has also worked with manufacturers to bring other essential antimalarial drugs through the WHO prequalification process. These drugs include rectal artesunate suppositories (RAS), sulfadoxine–pyrimethamine (SP) for intermittent preventive treatment in pregnancy (IPTp), and sulfadoxine–pyrimethamine + artesunate amodiaquine (SPAQ) for seasonal malaria chemoprevention (SMC).

In 2009, a WHO study [pdf] “demonstrated that a single dose of RAS 100mg, given as soon as a presumptive diagnosis of severe malaria has been made, can halve the likelihood of disability and death for young patients unable to access WHO-preferred first-line treatment for severe malaria, injectable artesunate … within 6 hours,” an MMV press release explains.

“To secure WHO prequalification for RAS, MMV supported both Cipla and Strides Pharma by providing technical guidance and know-how, supplying reference materials, co-funding development activities including bioequivalence studies, and helping prepare dossiers for submission,” the MMV website says.

In 2018, through MMV’s support, both Cipla and Strides Pharma secured WHO prequalification for their RAS products.

In addition to drugs that treat severe malaria, MMV has also invested in the development and manufacturing of drugs that prevent malaria, for use particularly for pregnant women to prevent newborn deaths due to malaria during pregnancy (SP for IPTp), and during the rainy season when transmission is highest in disease-endemic countries (SPAQ for SMC).

MMV has worked with partners, with support from Unitaid, to improve coverage of SP for IPTp to prevent malaria transmission during pregnancy in Africa, “as well as to improve global manufacturing solutions for quality SP, including the first-time prequalification of African manufacturers,” an MMV press release says.

In 2018, Fosun Pharma became the first manufacturer to obtain WHO prequalification for its SP for IPTp drug combination. MMV is now looking for additional manufacturers to support, particularly in Africa, that are interested to manufacture and seek WHO prequalification to supply SP for IPTp, to diversify and strengthen the supply chain for these essential drugs.

Another important drug combination demonstrating significant potential for the prevention of malaria is SPAQ for SMC, which according to a WHO policy recommendation has the potential to prevent 75% of cases of uncomplicated and severe malaria.

According to the MMV website, “seasonal malaria chemoprevention (SMC) is defined as the intermittent administration of full treatment courses of an antimalarial medicine during the malaria season to prevent malarial illness by maintaining therapeutic antimalarial drug concentrations in the blood throughout the period of greatest malarial transmission.”

In 2012-2013, MMV worked with Fosun to support the company’s efforts to obtain WHO prequalification for its SPAQ drug combination for SMC, and in 2014, WHO prequalification was granted.

 

Image Credits: Alena Koscalove / MSF, Damien Schumann / MMV, Ben Moldenhauer / MMV.

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