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Malaria

Improving quality diagnostic testing

Microscopy for malaria is technically demanding, and extending high-quality microscopy services to the community level has been difficult to achieve. Thus, the advent of rapid diagnostic tests (RDT) that can detect malaria antigens in a fingerprick blood sample has been an important advance. Their appropriate use will be critical in implementing WHO recommendations to confirm parasitemia in all patients over 5 being treated with ACT (Artemisinin Combination Therapy). From a single manufacturer 15 years ago, the field has grown to include over 50 manufacturers of such tests. This profusion of choice, and the variable quality of products reaching patients in developing countries, has made it difficult for national malaria control programs to determine which tests to purchase, and has left users uncertain whether they can always rely on the test result. The degradation of these tests on exposure to heat during shipping and storage compounds this problem. Mechanisms are urgently needed which can 1) indicate which RDTs are manufactured with the quality and performance needed by public health programs, 2) determine whether lots of RDTs are performing up to expectations after being shipped to countries but before dissemination to remote field sites, and 3) provide clinic technicians and health workers with a means to verify that the RDTs they are using are still of acceptable quality.

Once accuracy of these tests is assured, other issues of RDT usage can be properly addressed and the full impact of malaria RDTs, a potential revolution for the management of febrile disease in malaria-endemic regions, can be realized.

FIND and the WHO are collaborating to develop quality assurance systems to ensure that RDTs are working efficiently, are delivered to health workers, and that adequate materials to support training and good practice are implemented even in the remotest areas. FIND is also working to improve the next generation of malaria diagnostics.

Together with the WHO, FIND is implementing an accelerated three-stage solution to ensure that well-performing malaria RDTs are used in national disease control programs.

Stage 1: Product testing
Reference materials against which to test RDTs have so far not been available, and even manufacturers themselves are sometimes unsure of the performance of the tests that they release for sale. Geographic variability in the parasites themselves also means that these tests may underperform in some regions. Lastly, many of the RDTs are susceptible to degradation at temperatures commonly found in malaria-endemic countries.

Over the past two years, a globally-representative reference collection of blood from individuals infected with malaria has been established, and blood dilutions have been carefully made to standardize the concentration of malaria parasites in each sample. These materials have been characterized by PCR to establish parasite species and by ELISA to determine the concentration of parasite antigen in the dilutions. Nucleic acid sequencing of the relevant variable genes has been carried out. These blood samples form a stable reference panel that can be used to reproducibly evaluate RDTs. Rapid test manufacturers that operate according to international quality standards (ISO 13485:2003) have been invited to submit their RDTs for evaluation using the reference materials. Companies have enlisted more than four dozen products for testing. All of the submitted RDTs will be tested using the reference materials, and also subjected to heat-stability studies.

The product testing exercise is the result of extensive collaboration between WHO, FIND and agencies from all over the world. Reference materials have been created at Research Institute for Tropical Medicine in the Philippines, Pasteur Institute of Cambodia, Kenya Medical Research Institute, University Cayetano Heredia in Peru, University of Lagos in Nigeria, the Institute Pasteur in the Central African Republic, Institute Pasteur in Madagascar, Department of Medical Research (Lower Myanmar) in Myanmar, Ifakara Health Research and Development Centre of Tanzania, and the Centro Internacional de Entrenamiento e Investigaciones Medicas of Colombia. Genetic characterization of the parasites has been carried out at the Queensland Institute for Medical Research, and parasitologic characterization at the Hospital for Tropical Diseases in London. Species confirmation and Product testing is being performed at the US Centers for Disease Control and Prevention in Atlanta.

Stage 2: Lot testing
The good performance of an RDT in a controlled product testing scheme is no guarantee that other lots of this product, once shipped to the country of intended use, will perform as well as expected. Not infrequently, countries unknowingly purchase lots that are poorly performing, or that have been heat-damaged during transit. For this reason, mechanisms are needed for local or regional testing of purchased RDT lots before they are distributed for use. Since Health Ministries are currently purchasing RDTs in large numbers – over 50 million tests are being distributed this year – they need rapid access to information on the quality of the tests they are buying.

FIND and WHO are establishing 4 regional lot-testing sites that have the capacity to carry out rapid and high-quality performance evaluations of RDTs sent from anywhere in the world. These centers also provide a secondary service of storing and retesting the RDTs over time to ensure that they still function up to the time of their expiry date. All this information is rapidly transmitted to the submitting country so that decisions on the acceptability of purchased RDTs can be made. Lot-testing is currently successfully under way in the Philippines and Cambodia, where testing is performed for programmes as well as for procurement agencies working in Asia and Africa, and there are plans for additional sites in Kenya and Ethiopia to be functional by the first quarter of 2008. Other sites in the network are supported for national-level testing.

Stage 3: Positive control wells
It is vital that RDT quality can be checked and assured at the level of their use, often in remote clinics or in the hands of village volunteers. Ensuring accuracy saves lives by guiding correct treatment, and demonstrating accuracy gives both health workers and patients the assurance necessary to base treatment on the RDT result. Lack of confidence in results is a major impediment to current RDT-based programmes.

FIND and WHO are working with partners including the National Bioproducts Institute in South Africa and the Hospital for Tropical Diseases in the United Kingdom to develop stable wells containing the major target antigens of commercially-available RDTs. When available, these will provide a simple, low-cost method to test RDTs and ensure quality can be monitored from manufacture to the end-user, vital elements for a diagnostic programme focused on a high mortality disease. Transfer of this technology to a manufacturer is planned, and large-scale field trials of a prototype are anticipated from the end of 2008.

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