WHO, the Global Fund, and medical malpractice in malaria Amir Attaran, Karen I Barnes, Christopher Curtis, Umberto d’Alessandro, Caterina I Fanello, Mary R Galinski, Gilbert Kokwaro, Sornchai Looareesuwan, Michael Makanga, Theonest K Mutabingwa, Ambrose Talisuna, Jean François Trape, William M Watkins In 1998, WHO launched a new, high profile campaign to doubled childhood malaria death risk, and in some sites, Roll Back Malaria, with the stated goal to halve malaria increased it up to 11-fold in the youngest children. In East deaths worldwide by 2010.1 Achieving that goal requires and southern Africa, the proportion of children dying preventive interventions (eg, insecticide-treated bednets, from malaria doubled as chloroquine and later household insecticide spraying), but the main difference sulfadoxine-pyrimethamine resistance took hold from the between life and death for malaria patients hinges on 1980s to the 1990s, even as deaths from other causes appropriate treatments. Simply, each malaria case must declined.7 Elsewhere in Africa, chloroquine resistance be promptly and accurately diagnosed, and treated with increased the proportion of admissions to hospital and deaths from malaria by two-fold to four-fold.8 However, with nearly half the time to the 2010 deadline These links between drug resistance, treatment failure, now past, progress on effective treatment is so inadequate and finally death are not controversial. WHO concurs that that Roll Back Malaria is failing to reach its targets. Far chloroquine resistance is a “very likely” reason why from being on track to halve malaria deaths, WHO childhood malaria deaths in Africa are increasing, and that acknowledges that “RBM [Roll Back Malaria] is acting chloroquine “has become useless in most malaria-endemic against a background of increasing malaria burden”.2 Of the several reasons that could cause malaria deaths to sulfadoxine-pyrimethamine, which is often the replacement increase, one stands out most prominently: drug resistance for chloroquine, “is also widespread and its use [too] will in the deadly species of malaria, Plasmodium falciparum.
soon have to be discontinued”.9 That is borne out in WHO now writes of “global malaria control . . . being Kenya, where a decision 5 years ago (1998) to switch from threatened on an unprecedented scale” by continued use of chloroquine to sulfadoxine-pyrimethamine treatment is outdated drugs such as chloroquine, which is ineffective in most parts of Africa, and sulfadoxine-pyrimethamine, which treatment failure quickly reached dangerous levels.4,10 is becoming so.3 For example, in East Africa, surveillance and clinical trial data show that up to 64% of patients given chloroquine and 45% given sulfadoxine-pyrimethamine will therapies (ACT) as the best treatment option. The main fail treatment, and those figures are climbing.4,5 reason for treating malaria with combination therapy is When treatment failure becomes so frequent, malaria the same as for AIDS, tuberculosis, and leprosy, in which deaths rise greatly, especially in children. In West Africa it is standard practice: patients given two (or more) robust (Senegal), results of a 12-year community-based study6 and highly effective drugs are less likely to encounter drug showed that the onset of chloroquine resistance at least resistance and fail treatment—which brings both clinicaland public-health benefits. These benefits have now beenshown in a large meta-analysis11 of nearly 6000 patients, which shows that combining existing malaria drugs withan artemisinin both reduces patients’ risk of treatment Royal Institute of International Affairs, London, UK (A Attaran LLB); failure (by 75%), while lessening the pool of infectious Division of Pharmacology, University of Cape Town, Republic of parasites (gametocytes) that transmit the disease to South Africa (K I Barnes MD); Department of Infectious and Tropical others. In studies done on nearly every continent,12–19 ACT Diseases, London School of Hygiene and Tropical Medicine, UK successfully treats 90% or more of patients. That level of (C Curtis PhD, C I Fanello PhD); Department of Parasitology, Prince success can probably be maintained for a very long time, Leopold Institute of Tropical Medicine, Antwerp, Belgium since artemisinins have been used as Chinese traditional (U D’Alessandro MD); Malaria Foundation International, Atlanta, GA,USA (M R Galinski medicines for 2000 years, with no observed resistance.20,21 PhD); Faculty of Pharmacy, University of Nairobi, The superiority of ACT is now so established that of the PhD); Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand (S Looareesuwan five treatments WHO recommends for drug resistant Research Institute-Wellcome Trust Research Programme, Kenya P falciparum malaria, four are ACTs (the other is a “short- (M Makanga MBChB); East African Network for Monitoring term solution” for countries that cannot use ACT Antimalarial Treatment (EANMAT), Tanga, Tanzania immediately).3 ACT is now the preferred policy for WHO (T K Mutabingwa MD); Epidemiological Surveillance Division, and the Roll Back Malaria campaign as a whole: Ministry of Health, Kampala, Uganda (A Talisuna PhD); Institut de “Recently WHO has formulated policy that elevates Recherche pour le Développement, Dakar, Sénégal (J-F Trape MD); combination drug therapy to preferred first therapy for all Department of Pharmacology and Therapeutics, University of malaria infections in areas where P falciparum is the predominant infecting species of malaria. Combination therapy (CT) with formulations containing an artemisinin compound (ACT) is the policy standard . . .”22 THE LANCET • Vol 363 • January 17, 2004 • For personal use. Only reproduce with permission from The Lancet.
funding proposals in which inappropriate drugs weresought—and signed their approval. Those signatures follow a declaration that WHO “has participated throughout the . . . process” of developing the proposal to GFATM, and that it “reviewed the final proposal and [is] These decisions are indefensible. For WHO and GFATM to provide chloroquine and sulfadoxine- Data are median (range). See reference 24 for original data sources andmethods, which vary. *Range not available.
pyrimethamine treatments in the countries we cite as Parasitological and clinical failure rates for P falciparum
examples at least wastes precious international aid money, malaria in some African countries, 1996–2002 and at most, kills patients who have malaria. If one takesthe measured increase in childhood malaria mortality that However, WHO violates its own policy standard follows P falciparum drug resistance (two-fold to 11-fold) regularly. Most African countries reluctantly cling to and extrapolates it to populations in which GFATM is chloroquine, sulfadoxine-pyrimethamine, or the insignifi- cantly better combination of chloroquine and sulfadoxine- despite resistance (more than 100 million people in the pyrimethamine, because ACT is ten times more expensive four countries we name), then at least tens of thousands of and, therefore, unaffordable to them.2,23 When those same children die every year as a direct result. Those patients countries seek financial aid from the Global Fund for who survive will often become much sicker and require AIDS, Tuberculosis, and Malaria (GFATM) to purchase retreatment, at some further expense of time and money.
ACT, they are forcefully pressured out of it by govern- We do not exaggerate to state that, based on the ments such as the USA, whose aid officials say that ACT outcomes, there is no ethical or legal difference that is too expensive and “not ready for prime time”.24 WHO separates them from conduct otherwise condemned as acquiesces to this pressure to cut costs, and despite a medical malpractice (compare the case in which a doctor policy that names ACT as the gold standard of treatment, or pharmacist who, like these institutions, knowingly WHO signs its approval when GFATM funds cheap but furnished treatments that failed perhaps 80% of the time, ineffective chloroquine or sulfadoxine-pyrimethamine to while withholding the alternatives as “too expensive”). These problems might be discounted as aberrations, This series of errors is illustrated by several projects but for the evidence that they recur systematically. In currently supported by GFATM. Although GFATM addition to the four countries we name here, a WHO claims it supports only projects that use “proven and memorandum names five others where GFATM funded effective interventions” and “interventions that work”, in chloroquine and where, less than 2 years later, govern- Africa in 2003, it allocated more funds to purchasing of ments must already re-evaluate and move toward ACT.3 chloroquine and sulfadoxine-pyrimethamine than to Accordingly, there is often a disconnection between ACT.25 In January, 2003 (funding round 2), Africa was official policy, which favours ACT, and the reality created allocated US$16⋅1 million for ACT, $27·7 million for by WHO and GFATM, who routinely approve and finance inferior drugs. It is essential to understand why pyrimethamine (round 2). The corresponding amounts this has happened to repair the situation. for October, 2003 (funding round 3), were $2·2 million, To begin with, WHO has failed to define the medical norms for malaria treatment. Although there are carefully These budgetary differences are not insignificant. The crafted WHO model treatment guidelines for HIV/AIDS unit price differences between chloroquine ($0·13), and tuberculosis (the latter are in their third edition), to sulfadoxine-pyrimethamine ($0·14), and ACT ($1·00– date for malaria, recommendations are found only in 3·00) mean that patients given chloroquine and scattered WHO reports, rather than in official, sulfadoxine-pyrimethamine will outnumber those given comprehensive WHO malaria treatment guidelines.34,35 ACT by at least ten to one.2 Since GFATM plans this The lack of any such norms handicaps poor countries, budget for countries where chloroquine and sulfadoxine- who naturally hesitate to change their treatment policies pyrimethamine resistance in P falciparum is well advanced and request funding for ACT when that displeases the (table), many patients with malaria will fail treatment— powerful donor governments who warn them—usually in private—that ACT is too expensive.2,24 The same lack of Senegal has switched in 2003 from chloroquine to norms also causes WHO to miss opportunities to combination therapy for malaria treatment, but until this intervene and recommend ACT. That is probably why WHO country representatives, poorly informed by treatment, despite the known increase in child mortality Geneva, gave approval to GFATM applications for (two-fold to 11-fold) that it causes.6 In Kenya, GFATM ineffective drugs that violate WHO policy. rejected the government’s request to finance ACT, but later In theory, the GFATM’s Technical Review Panel should agreed to finance sulfadoxine-pyrimethamine, despite block proposals like this, but as the evidence shows, it often evidence that sulfadoxine-pyrimethamine treatment failure approves ineffective drugs for funding. For example, the exceeds 50% in some districts (eg, Kibwezi).4,28 In Ethiopia panel approved Uganda’s GFATM proposal with praise and Uganda, GFATM agreed to finance the combination for “strategies based on best practices”, when in fact the malaria treatment proposed (chloroquine and sulfadoxine- pyrimethamine—a pairing that WHO describes as “not pyrimethamine) is very plainly “not recommended” by recommended”—while falsely insisting that its action is WHO’s experts.29,36 Such decisions seem puzzling, until one “consistent with current treatment guidelines of WHO”.29,30 realises that the Technical Review Panel is not actually a These are very obvious errors of scientific and medical “technical” review panel. The four malaria reviewers on the judgment; and although WHO might be expected to Technical Review Panel are selected by a points-based spearhead a corrective intervention, the evidence suggests system, in which “technical knowledge . . . and ability to that it instead exacerbated the errors. In Kenya, Ethiopia, judge whether proposals are . . . scientifically sound” count and Uganda, WHO’s country representatives reviewed the for only 22% of that decision.37 By contrast, “familiarity THE LANCET • Vol 363 • January 17, 2004 • For personal use. Only reproduce with permission from The Lancet.
with international processes and . . . partnerships” and Finally, to ensure equally wrong-headed decisions do “familiarity with multisectoral approaches” count for twice not affect any intervention or disease again, GFATM as much (44%), even though it is hard to know what those should return to its original principles—and make the technical review panel a truly technical entity. Panelists The evidence therefore shows that the current practices should be selected on the basis of 100% technical and of WHO and GFATM are not adequate to safeguard the scientific knowledge, not 22%, as is true now.
best interests of patients with malaria. We offer several None of these recommendations imply new implemen- tation challenges for WHO and GFATM. Most have clear Above all, WHO should publish malaria treatment precedents in the HIV/AIDS or tuberculosis field, which guidelines that countries can depend on as authoritative means that equal treatment for malaria must be possible.
norms. Those guidelines should consolidate and broaden The scientific community must now watch future the knowledge in various WHO reports, in a single, developments closely, because numerous earlier warnings systematic presentation that is reviewed every year, and have been ignored. In 1999, several authors wrote in that addresses clinical algorithms, diagnostic methods, The Lancet to warn of an impending “malaria disaster”, malaria case definitions, standard treatment regimens, which is now apparent in rising malaria deaths.20 In 2000, definitions of cure, and so on.29,38 WHO can do this for one of the authors (AA) reported that aid agencies were malaria by copying its own actions on HIV/AIDS: first, funding ineffective malaria drugs, but the agencies denied WHO convened treatment specialists to debate and write that accusation and forcefully opposed a proposal to link the AIDS treatment guidelines, and second, it set the technical review to funding decisions.41,42 Similarly, our campaign goal of treating 3 million AIDS patients in recommendation to create a malaria Green Light developing countries by 2005.34,39 Importantly, that is the Committee has not been answered, either affirmatively or opposite sequence to Roll Back Malaria, which, in 2003 negatively, by WHO and GFATM in several months.
still does not have the treatment guidelines to reach the Rather, WHO has reiterated its earlier policy statements 1998 pledge of halving malaria mortality in this decade. favouring ACT—the same statements that were not Next, once they exist, WHO treatment guidelines heeded through these many errors—and established a new should be used to judge each proposal for malaria unit responsible for addressing tuberculosis and HIV drug treatment, so that only effective drugs receive GFATM funding. Although this recommendation seems obvious, The weight of evidence leads us to conclude that a crisis neither WHO nor GFATM believe it is within their exists, characterised by institutional inadequacies that mandate. Both agencies emphasise their roles as mere result in good policies for malaria control not being advisers or funders, while emphasising that selection of fulfilled. Although the inadequacies are easily rectified, a malaria treatments is properly done by countries—who, in risk exists that if WHO and GFATM do not act with our experience, are often pressurised by aid donors.28 The celerity, the reputations of both will be tainted such that fact that neither agency believes it has the obligation to rich governments lose confidence and cease funding them.
intervene and ensure that lives and money are not wasted That would deal a tragic blow not only to malaria is proof that a new entity is necessary. treatment, but also to the spectrum of efforts against We recommend that a new review committee be malaria, tuberculosis, and AIDS, which require and created, which is composed of independent malaria deserve billions of dollars wisely spent. The evidence now treatment experts, convened by WHO, and tasked by proves that money is often unwisely spent—very GFATM to review each proposal seeking finance for dangerous evidence indeed—and no delay is tolerable in malaria drugs. This Green Light Committee (so called because it controls the green light that lets a drug befinanced and supplied) has an exact precedent in Conflict of interest statementA Attaran advises Novartis on its not-for-profit partnership with WHO for tuberculosis. In 2000, outside experts created a Green the joint distribution of ACT (Coartem) in developing countries.
Light Committee, with WHO support, to review countries’ K Barnes is a recipient of grants from WHO and GFATM for malaria research, monitoring, and evaluation of ACT in South Africa. C Curtis is tuberculosis.40 Later, this Green Light Committee and the the recipient of research grants from WHO in which ACT is used.
U d’Alessandro advises GlaxoSmithKline on development and safety of GFATM integrated their procedures, and today, countries malaria drugs and vacccines. M Galinski is president of Malaria wanting drugs for multidrug-resistant tuberculosis submit Foundation International, which has received funding for advocacy of applications to both the Green Light Committee and Roll Back Malaria. G Kokwaro advises the not-for-profit Medicines for GFATM in a single envelope, so that the technical and Malaria Venture on development of new drugs, including ACT.
S Looareesuwan is coordinator of WHO’s SEAMEO TROPMED financial decisions affecting treatment happen together.
Network, and director for Thailand. T Mutabingwa and W Watkins are The need for a similar malaria Green Light Committee is Chairman and member of the secretariat, respectively, for the East African undeniable, since multidrug resistance in malaria is much Network for Monitoring Antimalarial Treatment, which has effectively supported studies using ACT. W Watkins advises GlaxoSmithKline ondevelopment of new malaria drugs, including ACT. Most of the authors Once the WHO treatment guidelines exist and the have participated in WHO-organised expert consultations or conferences malaria Green Light Committee is operational, its first task at some time. All authors write in their personal capacity and do not should be to retrospectively review all GFATM-funded represent the views of any institution or company.
countries in view of the guidelines. To let the full (usually 5 year) duration of financing run without updating the No funding was received from any source for the research and preparation standard of care, where justified by the evidence, would be unethical. This retrospective review will be easiest forcountries where GFATM funding has been approved butnot yet disbursed (eg, Uganda), although it should also be done for countries where disbursement is underway. If a Nabarro DN, Tayler EM. The Roll Back Malaria campaign. Science retrospective review finds that a country cannot use 1998; 280: 2067–68.
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