Rapid Diagnostic Tests in malaria case management

Rapid Diagnostic Tests in malaria case management Planning, Procuring and Implementing Suggestions for incorporation of malaria RDT-based diagnosis into proposals to the Global Fund Foundation for Innovative New Diagnostics (FIND), Geneva, Switzerland. WHO Global Malaria Programme (GMP) Geneva, Switzerland TDR, Special Programme for Research & Training in Tropical Diseases sponsored by UNICEF, UNDP, World Bank and WHO Geneva, Switzerland Modified from existing documents of the WHO Global Malaria Programme and WHO Regional Office for the Western Pacific

Introduction 1 Demonstration of malaria parasites is recommended prior to treatment with antimalarial drugs for most cases of malaria-like fever. In practice, this requires testing of blood by microscopy or by antigen-detecting malaria rapid diagnostic tests (RDTs). RDTs are now widely used in areas where good quality microscopy can not be maintained, particularly at small clinic and village level. The success of programmes using malaria RDTs to diagnose febrile illness relies heavily on the quality of the RDTs, and the way in which the RDT programme is introduced and supported. Aim of this document This document provides basic guidance on procurement and implementation of RDTs, and specifically aims to assist in the development of funding proposals incorporating RDT-based diagnosis into malaria case management, and the implementation of such programmes, including the re-programming of existing funds, where necessary. Main aim RDTs can be effective in guiding malaria treatment in fever case management. Introduction of RDTs must include careful planning for transport and storage, training, community sensitization, and quality assurance. Most fevers in malaria-endemic areas are not due to malaria, and provision must be in place for appropriate management of non-malarial febrile illness. Good performance data is now available on a range of RDTs to guide procurement decisions. Procurement decisions should also take into account the existing conditions in the area of expected use. A system for quality control and performance monitoring of RDTs should be in place, including lot-testing, which is now readily accessible to national malaria programmes. Budgets and funding requests for programmes incorporating malaria RDTs must adequately address the above issues, and the human resources necessary to implement them. 1 Assistance from the Global Fund to Fight AIDS, Tuberculosis and Malaria is acknowledged in the preparation of this document Suggestions for incorporation of malaria RDT-based diagnosis into proposals to the Global Fund Page 2 of 15

Part 1: Introducing RDT-based malaria diagnosis into national programmes 2 Most national programmes have relied heavily on clinical (symptom-based) diagnosis in the past, with microscopy used in larger clinics. As parasite-based diagnosis is introduced at smaller clinics and village level for case management, a large number of challenges arise in logistical management, and in managing the health-seeking and health-providing behaviour of patients and health workers. Many health workers and communities will have been taught that "fever equals malaria unless proven otherwise". Introducing RDTs will demonstrate that this is not the case. To have an impact on malaria case management, RDTs must be seen to provide an accurate diagnosis by both health workers and patients alike, that is, they must be as good or better than those relied on previously. A health worker will also need a good alternative to anti-malarial medicines for the management of parasitenegative febrile patients. To achieve and maintain confidence in RDT-based diagnosis, a functional quality assurance system must be in place (detailed elsewhere on this website). There must be adequate training of health workers, and widespread community sensitization. Knowledge of other causes of fever will be necessary to develop appropriate management algorithms for parasite-negative cases. At the national level, regulatory requirements may need to be developed to control the importation and use of malaria RDTs, and new procedures for storage, distribution and inventory management, such as those used for medicines, may need to be developed. If changing from a different product or mode of diagnosis, an adequate phase-out plan for this must also be developed. This requires a clear strategic plan to be developed well in advance of RDT introduction, with a clear timeline to ensure that the various components of the RDT programme are in place at the right time. A focal person, or persons, will be needed to coordinate the overall implementation plan and ensure that the various agencies that may be involved understand the process and their particular roles. To achieve this, funding for the programme must include a significant component for planning and coordination, sensitization/iec, training, quality assurance, monitoring and supervision, and logistics, in addition to procurement. Without this, much of the funds expended on RDTs may be wasted, and a loss of confidence in RDT-based diagnosis may hinder the process of strengthening appropriate malaria case management. An example of a national implementation plan is shown below. This will need to be modified considerably for each programme, preferably through a collaborative process involving all the major agencies concerned in its implementation. Budgeting for all the components of the programme at the outset is vital. An example of components to be considered in an overall budget is shown below. 2 This WHO document, available on www.wpro.who.int/sites/rdt, was developed by WHO with assistance from Management Sciences for Health (MSH) and the Uganda National Malaria Control Programme in the development of this document Suggestions for incorporation of malaria RDT-based diagnosis into proposals to the Global Fund Page 3 of 15

Summary of introduction plan (see following page) Program planning and management o Identify key stakeholders, and secure commitment for introduction of RDTs o Establish working group and develop terms of reference o Identify specific focal person(s) responsible for day to day oversight of the implementation plan o Develop a timeline, scope, and budget for implementation o Identify human and other resource needs, and a strategy for accessing them o Review and update, if needed, case-management algorithms for malaria and other causes of febrile illness Policy and regulatory issues o Develop appropriate regulatory documents if required o Register RDT products Procurement of RDTs o Develop product specifications and packaging requirements o Develop product short-list o Conduct quantification (estimation of needs) o Procure RDTs o Procure sharps boxes, gloves etc. Logistics o Develop distribution plan o Train logistics and storage personnel in handling and distribution of RDTs o Implement a system for data collection and information flows o Arrange for appropriate transport and storage o Review and strengthen inventory management, as needed o Develop a plan for discontinuation and disposal of other diagnostic supplies, if appropriate Quality Assurance o Develop mechanisms for assessing samples at a national level (lottesting), and regular (and random) testing at the level of use (e.g. microscopy-sentinel sites) o Implement post-marketing surveillance Training and communication o Develop appropriate training and supervision materials o Train health workers in case management and managing commodities o Train in RDT use o Develop and implement a program for community education/ sensitization Monitoring & Evaluation o Implement effective supervision and monitoring o Strengthen recording and reporting procedures Suggestions for incorporation of malaria RDT-based diagnosis into proposals to the Global Fund Page 4 of 15

RDT IMPLEMENTATION TIMELINE Sample timeline for introduction of malaria RDTs Example of necessary steps for implementation of Rapid Test (RDT)-based diagnosis in a national malaria programme. Programme planning and management Appoint malaria diagnosis coordinator(s) Policy recommendations Written MoH endoresment Guidelines Written MoH endorsement Case management of fever of unknown origin Case management of malaria RDT (and microscopy) quality assurance RDT transport and storage Decide districts for initial / phased implementation Fever management algorithm Written MoH endorsement Determine / designate transport and storage methods Regualtory issues Write Reg. Authority and NMCP roles Write registration criteria Register RDT procurement and logistics Select 3-4 products Samples for ease-of-use assessment Final decision on RDT Negotiate specifications with manufacturer Procurement Receive first batch (of staggered delivery) Distribution to field Procure gloves Procure sharps boxes Procure other associated materials Dependent on registration process later batch Quality Assurance Write sentinel site SOP Determine sentinel sites Set-up sentinel sites Set up Monitoring Lot-testing Post-marketing surveillance Training and communication Conduct case management training for fever Modify RDT instructions and training manual Field-test modfied training/instructions Training of trainers Community sensitization General health care providers education May be conducted earlier, or already in place Monitoring and evaluation Develop appropriate record forms and procedures Regular supervision Post-introduction programme review Suggestions for incorporation of malaria RDT-based diagnosis into proposals to the Global Fund Page 5 of 15

Malaria RDT implementation budget Below is an example of major components of a programme budget to be considered when introducing RDTs into a malaria programme. Without adequate provision for each of these factors, it is likely that an RDT-based diagnostics programme will fail to achieve its goals. These components should therefore be addressed in proposals for programme funding, or provisions should be made for them in collaborating programmes. Transport and storage Training, drugs / supplies for non-malarial fever Community education Training and supervision, instructions Monitoring accuracy in field Lot-testing and laboratory monitoring Procurement of gloves, sharps disposal containers Procurement of RDTs Suggestions for incorporation of malaria RDT-based diagnosis into proposals to the Global Fund Page 6 of 15

RDTs, the Global Fund, and funding proposals The Global Fund recognizes the importance of adequately funding implementation programmes to ensure that procurement of RDTs results in public health benefits. Countries may currently approach this in three ways. One approach is through applying for a new Global Fund grant: Develop detailed budgeted proposal for Round 9 application, ensuring provision for essential implementation funding within the budget or through other programmes http://www.theglobalfund.org/en/rounds/9/ Apply for implementation costs unbudgeted in current programmes by including a detailed, budgeted gap analysis in the Round 9 proposal. This option could assist the implementation of RDTs in case management when the other key related costs have not been included or sufficiently budgeted in a previous grant or national budget. The other approach is through requesting changes in current Global Fund malaria grants: Principal Recipients may request budgeting changes for funds in existing Global Fund malaria grants by contacting their Fund Portfolio Manager (FPM) at the Global Fund Secretariat. Requests can make use of savings from within the grant budget (for example, if there are savings due to paying lower prices for commodities than what was planned). A clear rationale, including a gap analysis together with clear proposed budget changes, should be included. Suggestions for incorporation of malaria RDT-based diagnosis into proposals to the Global Fund Page 7 of 15

Part 2: Update on WHO procedures for procurement and quality assurance of malaria rapid diagnostic tests Aim This note is based on documents from current WHO materials and recommendations regarding the use of malaria rapid diagnostic tests (RDTs) and upcoming future developments. It contains information useful for guiding procurement decisions, and for developing funding proposals and implementation plans. Background The introduction of malaria RDTs into control programmes is consistent with WHO recommendations that malaria case management be based on demonstration of parasites in most cases. 3 Malaria RDTs, when used well, can provide a rapid and reliable way to demonstrate the presence or absence of malaria parasites at all levels of the health service. However, evidence exists that current test accuracy in the field is variable, due to poor manufacture or exposure to high temperatures during transport and storage, and that negative results are frequently ignored by health care providers. To be effective, RDT introduction must be carefully planned, and the quality of testing ensured and demonstrated. Once this is achieved, RDT results can guide therapeutic decisions. Current Recommendations Quality assurance coordinator (coordinate all levels) Manufacture 1. Good procurement National level 2. Lot-testing Clinic-Level 3. RDT quality monitoring 4. Training and instruction Community 5. Use of results, and community education 6. Storage and transport 3 EN.REFLIST Suggestions for incorporation of malaria RDT-based diagnosis into proposals to the Global Fund Page 8 of 15

Planning for RDT introduction This requires a strategic plan with clear timelines to ensure that the various components of the RDT programme are in place at the right time. This is discussed in detail in Part One of this document. 1. Procurement It is recommended to procure based on performance in WHO malaria RDT product testing, carefully taking expected conditions of deployment and use into account. The report of round one of WHO product testing should be consulted for this information (www.wpro.who.int/sites/rdt/who_rdt_evaluation/), and a list of products and manufacturer contacts is also available on this site. These products are available direct from manufacturers, and may be procured through the WHO procurement 'WebBuy' system, but contacting WHO country or Regional offices. Box 1. Selection of RDTs based on performance in product testing should be guided by the following factors: Plasmodium species to be detected (P. falciparum only, pan-specific or other species-specific). Sensitivity and specificity Thermal (temperature) stability in intended conditions of storage and use Ease of use Requirement for post-treatment testing of patients Cost The manufacturer should provide: Evidence of viability of manufacturer Product support Sample products test for ease of use, etc. Agreement for replacement of failed product Appropriate packaging A good blood-transfer device An example procurement algorithm is shown below. The steps in the algorithm should be followed sequentially, using the malaria RDT product table available at www.wpro.who.int/sites/rdt The algorithm will rapidly reduce the list to a short-list suitable for procurement purposes. Manufacturers can then be approached to provide further documentation regarding the specifications in Box 1, if necessary. Sensitivity and specificity are difficult to assess, as they are dependent on the parasite density and other characteristics of the population tested, on RDT preparation and interpretation, and on the quality of the reference standard. Detection rates in the WHO product testing report will be a useful guide to this. Data on test accuracy obtained from the manufacturer and field studies is important, but should be interpreted with careful consideration to the context in which the testing took place. In order to evaluate test sensitivity and specificity after deployment, lottesting and field monitoring are essential. Thermal stability data is available from the WHO product testing report, and should also be obtained from the manufacturer, and compared with conditions of intended Suggestions for incorporation of malaria RDT-based diagnosis into proposals to the Global Fund Page 9 of 15

transport, storage and use. The parasite density (antigen concentration) of the standard used to assess stability should be noted, as a heat-damaged RDT may still detect samples with high parasite density. Staggered delivery is good policy (splitting delivery from the manufacturer into 2 or 3 batches several months apart), as it reduces the burden on central storage facilities, and allows new products to be received nearer the expected time of use, shortening storage times and effectively lengthening the shelf-life of the overall procurement. 2. Lot testing: Pre- and post-purchase It is recommended that all lots (batches) of RDTs be tested before deployment to the field. A 'lot' to be tested is normally defined as a production run using a particular batch of monoclonal antibodies and nitrocellulose. They are normally defined by number in this way by the manufacturer, and usually consist of 40,000 to 80,000 tests. Lot-testing can be done: (1) before purchase, directly arranged with the manufacturer and a lot-testing centre (note: WHO WebBuy can not arrange this) (2) after purchase, before distribution to the field. Why lot-test? Lot-lot variation noted in most products Ensure no damage during transport to country Need to convince clinicians / users / regulatory authorities that tests are working Lot-testing can be facilitated by WHO and FIND. It is currently performed at three regional lot-testing centres, and some other countries also have capacity for this: Malaria RDT Quality Assurance Laboratory Research Institute of Tropical Medicine (RITM) DoH Filinvest Compound, Alabang, Muntinlupa City Philippines Laboratory of Molecular Epidemiology Pasteur Institute of Cambodia #5, Monivong Blvd, PO Box 983 Phnom Penh, Cambodia Ethiopian Health and Nutrition Research Institute (EHNRI) Gulele, near St. Paul Hospital Addis Ababa, Ethiopia Requests for more information related to lot-testing should be made to: mal-rdt@wpro/who.int, prabhat.deva@finddiagnostics.org and cunninghamj@who.int Lot-testing is currently conducted at the above laboratories at no charge, but the sending institution must cover transport costs. At least 2 weeks prior notice should be given before shipping the RDT tests. Testing is performed on a sample of approximately 125 P. falciparum-only RDTs or 175 combined P. falciparum and pan-specific RDTs, for each production lot in the order. The lot-testing centres follow procedures developed by WHO for this purpose 4, 4 WHO (2006). The role of laboratory diagnosis to support malaria disease management: Focus on the use of rapid diagnostic tests in areas of high transmission. Geneva, World Health Organization. Suggestions for incorporation of malaria RDT-based diagnosis into proposals to the Global Fund Page 10 of 15

and usually return initial results within 5 working days. Retained RDTs are then monitored every 3 months throughout the shelf-life at close to the manufacturer's recommended maximum storage temperature, and the procuring agency informed of results throughout the shelf-life. Further details can be found at www.wpro.who.int/sites/rdt 3. Monitoring performance in the field Field monitoring is difficult, partly due to the inherent problems of accuracy of field microscopy, with which RDTs must be compared. At present, the following procedures are recommended: Compare RDT results with expert light microscopy. RDTs and blood films (BF) should be taken from the same patients in selected health facilities where RDTs have undergone typical storage and distribution. e.g. Every month, 40 RDTs (20 positive and 20 negative) may be crosschecked against the corresponding 40 BF obtained from the same patients and examined by expert microscopists. Where >15% discordant results occur, a more detailed field evaluation should be rapidly performed or the remaining RDTs should be returned for laboratory testing (see 'lot-testing' above). Expert microscopy may be available at the 'sentinel' sites used for monitoring therapeutic efficacy of antimalarial medicines, or at the central/regional reference laboratory. It is important that the microscopists selected for the evaluation of RDT performance have high competency. In addition, it is important to supervise the health workers performing RDTs on a regular basis in order to evaluate health worker capacity for interpreting a set of prepared RDTs assess health worker technique in RDT preparation review diagnosis and treatment records ensure good blood safety practices are maintained ensure sufficient supplies are in place for management of malarial and nonmalarial fever 4. Training and instructions for users Prior to introducing RDTs, appropriate training of health workers is needed and instructions and materials should be clear, in locally-appropriate language, and fieldtested. The WHO and partners have developed generic job-aids and a training manual for health workers, based on trials in Asia and Africa with several partners. These materials are available in English and French, and can be adapted to other languages. Examples are down-loadable from www.wpro.who.int/sites/rdt. 5. Use of results and community education There is wide evidence that RDT (and microscopy) results are frequently ignored when treatment decisions are made. To address this, it is essential to: Ensure and demonstrate the accuracy of the RDTs (through the quality assurance processes above) Suggestions for incorporation of malaria RDT-based diagnosis into proposals to the Global Fund Page 11 of 15

Provide algorithms for appropriate management of parasite-negative cases (nonmalarial febrile illness), and train health workers in their use Provide health workers with the means to manage parasite positive and negative cases appropriately Educate (sensitize) the community on the importance of parasite-based diagnosis Malaria diagnostic programmes therefore require an approach that addresses fever management, not just malaria management. To have a successful programme, it is essential to move beyond a narrow malaria-only approach. 6. Storage and transport Standard supply management procedures should be applied to minimize storage times and exposure to extremes of temperature, similar to those for the handling of drugs. These include staggered delivery of large purchases, first-expiry / first-out stock management, controlled-temperature centralized storage, and avoiding storage in peripheral facilities with no temperature control. Direct sun exposure should be avoided, and transport coordinated to minimize exposure to temperatures exceeding the manufacturer's recommended storage temperature. Suggestions for incorporation of malaria RDT-based diagnosis into proposals to the Global Fund Page 12 of 15

RDT procurement: example algorithm for selecting a malaria RDT Parameter Decision process Decision 1. Plasmodium species to be targeted Distinguish non-pf from Pf or mixed? Yes No Combination test HRP2- pldh HRP2- aldolase pldh- pldh Pf-only test HRP2 pldh (may be combined with pan-specific pldh) 2. Expected areas of use Store and use in tropical/hit environment without temperature control Yes No High-stability High stability demonstrated, and specified temperature e.g. 35 C Storage temperature less critical Accept lower stability and <35 C specified storage 3. Likely clinical scenarios Likely to use for re-testing soon after treatment / treatment-monitoring Yes No Target non-persistent antigen pldh-detecting for P. falciparum Antigen persistence not critical HRP2 or pldh for P. falciparum 4. End-user For use by health workers outside medical laboratories Yes Simple format, all-inclusive Cassette design, few steps, lancet, swabs etc included in package No Design less critical Include dipsticks Test-only packaging Select, from WHO malaria RDT product testing report, RDTs that fit the prioritization chart above and have sufficiently high detection rate, low false positive rate and invalid rate. Sometimes preferences from different sections of the above algorithm will be incompatible, in which case prioritize the importance of the categories above for your programme. Suggestions for incorporation of malaria RDT-based diagnosis into proposals to the Global Fund Page 13 of 15

Next Step: Finalize short-list of suitable RDTs CHOOSING SPECIFIC PRODUCT FROM SHORT-LIST 1. Contact manufacturers and request: 1. Quoted price (include necessary accessories, delivery to country, and staggered delivery in 2-3 batches over 12 months). 2. Heat stability data as evidence of manufacturer's stated storage temperature and shelf-life. 3. Sample of product to assess format, ease of use, and compatibility of other materials with health system requirements. 4. Information on box size; e.g. how many fever cases expected in 3 months (if less than one box, request reduced box size). 2. Assess other experience If possible, obtain written assessments of field experience from other countries / programmes that have experience in using the product. Make preliminary procurement decision, then consider 3. Options to improve implementation: 1. Negotiate replacement of product if supplied product fails lot-testing after delivery by a method approved by manufacturer / WHOcoordinated laboratory. 2. Develop appropriately-formatted instructions in appropriate language and consider their inclusion in kits at the manufacturing site. 3. Negotiate delivery dates for staggered delivery to reduce in-country storage times and ensure long (e.g. 18 months) shelf-life after delivery. 4. Organize lot-testing prior to dispersal to the field Suggestions for incorporation of malaria RDT-based diagnosis into proposals to the Global Fund Page 14 of 15

FURTHER INFORMATION Global Fund Ten Quick Facts on procuring malaria RDTs: http://www.theglobalfund.org/documents/psm/10quickfactsrdts_en.pdf WHO good distribution practices and WHO good storage practices for pharmaceutical products: http://www.who.int/medicinedocs/collect/medicinedocs/pdf/s6156e/s6156e.pdf and http://whqlibdoc.who.int/trs/who_trs_937_eng.pdf#page=191 Global Fund call for Round 9 Proposals: http://www.theglobalfund.org/en/rounds/9/ WHO information site for malaria rapid diagnostic tests: http://www.wpro.who.int/sites/rdt Training materials, job-aids (instructions) and guides: http://www.wpro.who.int/sites/rdt/documents/list.htm For Lot testing: Pre- and Post-purchase: http://www.wpro.who.int/sites/rdt/who_rdt_evaluation/ and contact: mal-rdt@wpro/who.int, prabhat.deva@finddiagnostics.org and cunninghamj@who.int Results of Round 1 of the WHO malaria RDT product testing programme: http://www.wpro.who.int/sites/rdt/who_rdt_evaluation/ Suggestions for incorporation of malaria RDT-based diagnosis into proposals to the Global Fund Page 15 of 15