All published and unpublished documentary evidence surrounding the antimalarial drug policy change were reviewed and the health system context within which they were made. These data were supplemented by the authors' observations of the policy change process (several of the authors were actively involved and attended many of the relevant meetings). Information has been structured to capture the timing of events, the difficulties and hurdles faced and the resolutions reached to the final implementation of a new treatment policy.
Case description
Zambian context prior to policy change
Since the late 1970's, there was a significant increase in malaria-related morbidity and mortality seen at health facilities nationwide [6]. Direct attribution of causes for the resurgence of the malaria burden is hard to define, but it was widely held that the disease transition was a result of a combination of economic, prevention and treatment failures. The economic crisis that began in the early seventies led to a re-prioritizing of local government expenditure, resulting in budget cuts in most sectors including health. The insecticide-spraying programme, which had been a major component of malaria control during the fifties and sixties, had to re-deploy spray men to other functions or lay them off altogether. The end of the global malaria eradication campaign and the WHO's recommendation for worldwide cessation of DDT use in 1973 led to DDT being banned from use in IRS in Zambia. This dealt a final blow to the public sector malaria control programme in Zambia [6]. By the second half of the 1980s, the health budgets of the private mining companies also began to face cuts, leading to reductions in spraying coverage rates, and the mines no longer added buffer zones to their spraying programme and ceased spraying altogether in 1990. Against a background of a collapsed prevention programme and declining health sector financing the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic grew rapidly in Zambia [7]. As with other southern African countries facing similar collapses in the health sector financing and a growing health system burden posed by the HIV epidemic, the emergence of resistance to CQ in Zambia represented a public health disaster.
Drug sensitivity evidence from surveillance data
Nineteen studies examined the efficacy of CQ at sentinel sites across Zambia between 1995 and 2000 using the World Health Organization (WHO) 14-day efficacy protocol [8]. In 1995 treatment failure rates (combined early and late treatment failure) in children under the age of 5 years ranged from 5.4% to 13.6% at 8 sites. By 1999, the failure rates had risen to between 24.1% and 44.0% across 10 sites [6]. Between 1995 and 1999 day 14 treatment failure rates with SP, the second line drug for uncomplicated malaria at the time, were low (0–4.2%). Two studies evaluating the efficacy of CQ were undertaken between 1999 and 2002 at six sites documented day 14 treatment failure rates were between 25.9% and 52.0% [9]. Corresponding day 14 treatment failure rates for SP during this period were between 3% and 7%. After the studies in 2002, a decision was made, based on ethical reasons, to halt further efficacy testing of CQ.
The policy change process
In recognition of the complexity of changing first-line therapy for malaria, a multidisciplinary Drug Technical Advisory Group (DTAG), a sub-group of the National Case Management Working Group with representation from the pharmaceutical, medical, research, policy and District Health Management Teams (DHMT) was established in the first quarter of 2002 (Figure 1). In addition, multiple external technical missions to the programme conducted by partners such as the WHO RBM programme and the United States Agency for International Development (USAID) provided technical support to the DTAG. The DTAG had two major tasks: a) developing the technical framework for treatment policy change; and b) designing an advocacy strategy for the new treatment policy including resource mobilization (financing for the policy change and funds for procurement of the antimalarials, among others). The DTAG provided feedback and reported to the National Malaria Taskforce and the Minister of Health. In addition to improving the malaria control programme, this policy change process was expected to strengthen the performance of other key health sector support functions such as procurement and supply, drug regulation, communications and health management information systems.
In April 2002, the DTAG reviewed the scientific evidence for policy change [10]. The evidence included the rising morbidity and mortality statistics, the CQ and SP drug efficacy studies and research evidence from neighbouring countries, notably in South Africa [11]. At this point in time, there had been no clinical efficacy studies of possible ACT replacements undertaken in Zambia as the only drugs that had been studied in Zambia up until then were CQ and SP. CQ resistance was approximately 60% (20–80% depending on site), well beyond the WHO's recommendations for changing national malaria drug policy. The DTAG concluded that immediate action was required to replace CQ as first line therapy and increase access to curative services and strengthening the health system's ability to deliver appropriate care. As such the policy addressed issues related to laboratory diagnosis, logistics and supply chain management, and behavioral change and communication.
The DTAG considered several factors regarding the replacement options to CQ, including the expected pace of resistance emergence, tolerability, safety, and procurement costs. Monotherapy options were considered. For example, SP was considered an easy option because it was already in use as the second line antimalarial and could be administered as a single dose treatment with a relatively high safety profile in all age groups. However, the DTAG were persuaded that SP was not a long-term option because parasitological resistance was already appearing in parts of Zambia [9, 12] and the arguments for combined therapy were important to the DTAG in an effort to delay the future emergence of resistance. At the time of the policy change, SP resistance was low [12] but due to the fact that this drug was the treatment of choice for children weighing less than 10 kg and pregnant women, the DTAG decided to preserve the use of the drug. Additionally, SP is not truly combination therapy and hence it was not a good choice for the replacement of CQ. Amodiaquine was not considered as a serious contender as a replacement therapy, either as a monotherapy option or in combination with artesunate, because of its structural similarity to CQ and the potential for cross-resistance. Halofantrine and mefloquine were considered but due to safety concerns [13], given the likelihood of substantial unsupervised use, these drugs were not selected. Quinine was reserved for the management of severe malaria and treatment of malaria in pregnancy. By a simple process of elimination from the limited available options, in March 2002 the DTAG recommended AL for the treatment of uncomplicated falciparum malaria [14]. AL was the only fixed dose combination available at the time, had proven therapeutic efficacy even against multi-drug resistant parasites [15–17], and was also considered to have the least potential of developing drug resistance [18]. The fact that AL additionally had a comparative price advantage, offered through the differential pricing agreement between WHO and Novartis Pharma AG, made this treatment option more appealing.
Nevertheless, there remained several concerns about the adoption of ACT for Zambia. Members of the DTAG were cautious about the introduction of a new drug with limited published data on its safety profile. Four further concerns were raised by the DTAG: First, AL was at the time not recommended for use in pregnant women or children weighing less than 10 kg, two of the most vulnerable groups. Second, AL had a complex dosing schedule which included the need for a fatty meal to enhance absorption of the lumefantrine component. Third, AL had a short shelf life of 24 months. Finally, AL, despite the preferential pricing, still cost 40 times more than CQ.
It was estimated that the cost of supplying AL to cover all malaria cases in Zambia in 2002 would have exceeded the finances available for the overall Basic Healthcare Package for the entire country. Additionally, the Ministry of Health was struggling at the same time with the conflicting priority need to launch an antiretroviral therapy programme in-line with the WHO's 3 × 5 strategy [19]. Concerns were also raised about the sustainability of AL supply from a single supplier who might not scale-up production to meet the increased demand.
Despite these legitimate concerns regarding lack of previous experience with AL, financing and sustainability, alternative options were few and a definitive decision was urgently required. In October 2002, AL was officially adopted as the future first-line therapy for Zambia, a decision that received a strong political commitment from the Minister for Health.
Policy change preparatory phase
From October to December 2002, the DTAG, with regular support from the Minister of Health, agreed to implement the policy decision in the most expedient manner and decided upon a phased implementation plan leading to complete national coverage. The plan [14] proposed that seven early implementation districts would be the first recipients of AL and training in its use allowing lessons learnt to adapt the implementation strategy in the second phase involving 28 districts and final expansion in the third phase to the remaining 44 districts across Zambia. This ensured that once a decision had been announced action was taken, albeit in a pilot phase and allowing time for the assembly of necessary financing. At this stage, the functions of the DTAG were redefined and included two essential components: a) a case management advisory group (guidelines, training, job aids); and b) a drug transition team (procurement, forecasting, distribution, training, supervising implementation, and outcomes monitoring).
In order to fast track the policy implementation process and avoid a potentially protracted formal debate and approval process within the Zambian Parliament, and since malaria control was considered a statutory activity, it was agreed that the policy change should be reconciled within the National Health Services Act of 1995 [20]. An Information Cabinet Memorandum was prepared in order to notify the Cabinet, as per government procedure.
Further regulatory changes were required to re-register Coartem® (AL) from the 4-dose regimen in the private sector to a 6-dose regimen, the WHO recommended regimen, for public sector use. A waiver was obtained through the provision in the National Pharmaceutical Act allowing for extension of a drug label. The Zambia National Formulary Committee was approached by the DTAG to endorse the use of AL and its inclusion in the Zambia National Formulary and Essential Drug List with the status of a first-line antimalarial drug. As a condition of this process, the Poisons and Pharmacy Board recommended the design of a strategy for monitoring the safety of ACTs through post-marketing surveillance, as these were relatively new drugs. The Pharmaceutical Association of Zambia in collaboration with the Poisons and Pharmacy Board were tasked to mobilize technical and financial support for this programme.
Although the introduction of health reforms in Zambia led to the decentralization of Primary Health Services in Zambia, making malaria control an integral component of the Primary Health Care package, the program also benefited from increased investments of up to $20 per capita. However, the disadvantage was that the cost of deployment of certain drugs such as AL was well beyond the budget for the package. This led to high levels of discomfort amongst the donors with fear of introducing a vertical program but nonetheless a simultaneous heightened determination for resource mobilization.
Following the necessary legislative and regulatory approvals and revisions, the immediate challenge for the DTAG was to find external financial support to complete implementation of the policy. The call for proposals in January 2002 for Round 1 of the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) represented a unique opportunity to secure the necessary funding to effect policy change. All elements, including a forecasted drug need, necessary to implement the drug policy change were assembled into a proposal to the GFATM. The Zambian Government submitted a four year proposal requesting 36 million US$ for malaria control from the GFATM, of which, in the first year 4 million US$ were committed for the procurement of AL and 400,000 US$ to support implementation of the new policy mostly through strengthening of laboratory malaria diagnostic capacities [14]. The application was one of a few successful first-round GFATM submissions for malaria control in Africa [21]. The GFATM decision was made in April 2003 and the funds were released to the Zambian Government in August 2003 (Figure 1).
Since the Novartis Pharma AG AL product was the only pre-qualified form of AL available at the time, a waiver had to be obtained from the Nation Tender Board to allow for single sourcing. The first order was placed and procured through the special WHO-Novartis public sector supply mechanism and the shipment arrived at the Medical Stores Limited in Lusaka, the Government's medical supply agency in September 2003 (Figure 1). The distribution, based upon monthly estimated demand by district, began in October 2003 and districts were expected to request additional stock in concert with consumption from the Medical Stores Limited. In February 2003, before the arrival of GFATM funded drugs, the non-governmental organization, Médecins Sans Frontières (MSF), donated 800,000 AL tablets to assist with the early implementation, Phase 1, seven districts. Phase 2 involved the deployment of AL to an additional 28 districts between July and December 2003. Funds to ensure the implementation of Phase 2 were made available from the flexible, government-driven, Heavily Indebted Poverty Countries (HIPC) resources and the GFATM funds. Subsequently, nationwide deployment (Phase 3) took place in the first quarter of 2004 funded largely by the funds provided by the GFATM.
The private sector played a cardinal role as 20%–30% of sick patients seek treatment from private practitioners in Zambia. In addition, local manufacturers were involved in the packaging and distribution of chloroquine. A private sector access strategy was therefore developed and funds to implement the plan were mobilized in the GFATM Round 4.
Policy change implementation phase
Two principal guidelines addressing malaria case management were used in Zambia prior to the malaria drug policy change: the Integrated Technical Guidelines (ITG) for front-line health workers [22] and the Integrated Management of Childhood Illness (IMCI) guidelines [23, 24]. Through technical consultation between January and May 2003, a final draft of malaria-specific NMCC guideline, titled "Guidelines for the Diagnosis and Treatment of Malaria in Zambia", was developed to reflect the new treatment policy for uncomplicated malaria [25]. The IMCI guidelines were revised to incorporate the new drug policy and were inserted as a change into the IMCI algorithms. The ITG guideline was updated by the inclusion of an addendum in February 2003. An additional job aide was developed, with support from Novartis Pharma AG, in the form of AL treatment dosage wall charts and was distributed to the districts alongside the drug supply.
A process of cascade in-service training was initiated to introduce the final draft of the National Malaria treatment guidelines, which began with three sub-national training of trainers (TOT) trainings, each including key members of the District Health Management System Teams (DHMT). Following the sub-national training between June and July 2003, district-level training was proposed at the convenience and funding arrangements of respective DHMTs. Trainings at the district-level occurred between November 2003 and February 2004 (Figure 1). The training involved an initial orientation programme for managers, followed by a programme for referral facilities, and then two-day workshops for front-line health. The training and orientation of district health workers was synchronized with the phased AL deployment. During the training, participants were provided with individual and institutional copies of the National Malaria Treatment Guidelines [26, 27, 27].
A detailed information, education, and communication (IEC) strategy was developed, which included a series of TV and radio programs highlighting the policy change. Job aids, dosage charts and posters were developed and distributed to all the health facilities in the countries. The challenge was to ensure consistency in the messages particularly during the pilot phase.