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Organizations such as Doctors withoutBorders (Médecins Sans Frontières, orMSF) provide emergency medical

assistance to populations that do not haveaccess to medical care. In the various settingsin which MSF works, the absence of suitablediagnostic tests is far more the rule than theexception. The need for reliable diagnostics isclosely linked to the need for safe and effectivetreatments, and many of the diseases consid-ered ‘neglected’ in terms of treatment areequally neglected in terms of diagnosis. In thecase of sleeping sickness, for example, existingtreatments are highly toxic and can kill up to10% of patients1; an accurate diagnosis musttherefore be made before starting treatment. Inthe case of malaria — which kills more than 1 million people a year2 — misdiagnosis of thedisease from clinical signs alone3,4 is often aproblem. The need to avoid overprescribingantimalarial drugs, to minimize costs and therisk of developing resistance, reinforces theneed for an adequate diagnostic test.

MSF and other humanitarian organizationsface similar challenges in diagnosing othermajor diseases in resource-poor settings,

notably tuberculosis, HIV in infants and HIV-associated infections such as cryptococcalmeningitis. The lack of suitable diagnostictests for use in the field means that the identi-fication of many diseases is based solely onclinical symptoms. The long list of diseaseswith no field-adapted diagnostic tools includesleishmaniasis, shigella, typhoid and bacterialmeningitis. MSF is attempting to address theseneeds by exploring how available technologycan best be used, either by improving existingtests or by developing new, field-adapted ones.

What is needed?The reasons for the gaps between need andavailability are manifold. In some cases, exist-ing tests are not sensitive or specific enough, orsome of the fundamental biology of the diseaseis still not known. In other cases, technologiesdo exist but are too complex, too expensive ornot suitable for remote settings with poorinfrastructure. The technically challenging,painful and risky diagnosis of meningitis andsleeping sickness through lumbar puncture isa good example. The gaps between field needsand available solutions are large, but, as we

argue here, they can be effectively reduced byadopting a ‘needs-based’ approach to researchand development and by making use of exist-ing resources.

As with medicines for neglected diseases,the development of diagnostic tools for use inresource-poor settings is often thought to havelittle market incentive for private companies.Decision-making in the pharmaceutical andbiomedical industries is increasingly driven bypriority-setting based on expected marketreturns5. This priority-setting puts the needs ofthe company shareholders before those of thepatient. The experience we document hereshows how, by combining the specific needsidentified by MSF in the field with existing sci-entific expertise, the development of appropri-ate diagnostic tools can be accelerated. Byspeeding up this process we can keep costsdown, and thereby increase the likelihood thata test will be developed or marketed. Suchopportunities should be attractive to both testproviders and purchasers in the private andpublic sectors.

An example of such a needs-based product-development strategy is the development of a

Improved rapid tests formalaria are needed to

accurately diagnoseinfection and to avoid over-

prescription of drugs.

Neglected tests for neglected patientsAlternative ways to develop diagnostic tools for use in resource-poor settings can, and do, exist, argue Martine Usdin, Martine Guillerm and Pierre Chirac of Doctors without Borders.

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new rapid diagnostic test (RDT) for malariathat is now in the final stages of field evalua-tion. Currently, MSF performs more than 4 million malaria RDTs a year, mainly inAfrica and Asia. Specific problems with exist-ing tests were previously identified by MSFstaff. For example, the current ‘gold standard’,smear microscopy, requires trained techni-cians and careful quality-control, which is notalways possible in the field. Existing RDTsbased on detecting the malaria parasite proteinHRP2 in fingerprick blood were seen to beuseful and cost-effective, but are limitedbecause HRP2 proteins circulate for months in the blood after cure and therefore the testcannot distinguish between an old, resolvedinfection and a new one. Nor do they detect allstrains of malaria.

In 2003, MSF decided to coordinate thedevelopment of an alternative test, by startingwith a precise definition of what was needed inthe field — what type of test, who would use it,and how the information obtained would beintegrated into subsequent medical decisions.It is tempting to make the most elegant, infor-mative and cutting-edge device. However, thedesign goal was a test most adapted to the set-ting in which it was to be used — mainly inmalaria-endemic areas in Africa, where heatand humidity, ease of use and cost are impor-tant concerns. The needs in Asia are different:there is more than one endemic parasitespecies and different levels of infection andresistance in the populations that make addi-tional information, such as the strain of para-site, desirable.

Everyone’s happyMSF brought together scientists, field doctorsand manufacturers who applied their expertiseto the development of an alternative test basedon the detection of the malaria parasite enzymepLDH in the blood. This test is more suited fordiagnosing malaria in Africa than the HRP2test because, among other things, pLDH levelsdrop rapidly with clearance of parasites, allow-ing clinicians to distinguish between patientswho are still infected with malaria after treat-ment, and those in whom fever symptoms haveanother cause. The possibility of a pLDH testwas identified by MSF from published paperson the characterization of a panel of pLDHmonoclonal antibodies6. After several roundsof discussions to define the medical needs offield clinicians and the integration of the resultsinto patient care, MSF contacted the US devel-oper of the antibodies, Michael Makler of thecompany Flow Inc. in Portland, Oregon, toexplore the possibility of using his reagents.

The initial feasibility of the project wastested by other leading scientists who gaveadvice and performed in vitro validation. Theantibodies were then offered to three manu-facturers who worked to optimize the test for-mat for ease of use and performance, anddeveloped three independent versions of thepLDH test. These were then evaluated in MSF

field projects. Opening up the market to morethan one company encouraged the manufac-turers to pursue development of a qualityproduct that is adapted to field conditions,while maintaining the price at an accessiblelevel. The entire development process, fromidentification of diagnostic needs through tofield evaluation, was completed in less thantwo years, at the relatively low cost of about€80,000 (US$100,000), most of which wentinto field trials and was provided by MSF.Development of a new test can typically costmany hundreds of thousands of dollars7.

This unusual development process hasshown that products that are needed in thefield, especially those for which there is not a‘traditional’ or high-paying market, can still bedeveloped in an efficient, commercially viableand mutually beneficial way. The developmentof this test differed from a typical diagnosticdevice in that low cost and field specificationswere the main considerations fromthe outset, rather than market-driven (how much can we charge?)or technology-driven (what is themaximum information that we candeliver?) processes. The develop-ment team (MSF, Michael Makler,three different manufacturers, scientific and technical consultants, and fieldusers) were guided at all times by these specifi-cations. Thus, although all the players had their own motivations for participating,whether it was altruism, profit, need, curiosityor otherwise, all parties were working towardsthe same goal.

A successful modelThe development of the malaria test built bothon existing research (the use of pLDH as amarker for malaria infection) and existing tech-nologies (immunochromatographic rapidtests). This created an efficient developmentmodel that we believe can be replicated else-where. In universities and industrial labs thereare many �80 �C freezers or bottom drawers offiling cabinets containing antibodies, constructsor designs that have been shelved owing to lackof funding, interest or conflicting corporate orresearch priorities. MSF and others can act aspartners in guiding the development of these‘leftover’ products into appropriate tools.

But large doses of goodwill and unlimited

access to freezers are not enough. In mostcases, developing such tests requires cash andinfrastructure, resources that are not alwaysavailable. However, if the test is based on asolid assessment of the field needs and capa-bilities, it is more likely to be useful and theresources will be well spent. This happenswhen medical care drives the development oftests, rather than doctors being forced toadapt their medical care to the existing tools.The pLDH development model was a success-ful one, and it can and should be applied inother contexts.

MSF’s experience during the developmentof this new malaria test shows how commoninterests can be fostered to bridge the gapbetween the needs of product developers andend users for the ultimate benefit of allinvolved. Given the long list of diseases withneglected diagnostics, there are many moreopportunities to act and to make a difference.We appeal to scientists to respond to suchopportunities by making existing reagents andideas available for the development of diag-nostic tests for these diseases. Such projectscan make financial sense and have a hugeimpact on serious health issues, often withoutthe enormous budgets of traditional develop-ment models.

We have described just one of manyapproaches needed to address the gaps indiagnostics; others include better use of exist-ing reagents, training of local technicians inthe field and a more creative and flexibleapproach to traditional product development.

We recognize that there are otherfactors that limit the developmentof new tools. In many cases, intel-lectual-property restrictions posea significant barrier. There arealso important issues in ensuringthe quality of the tests and indeveloping international stan-

dards for diagnostic tools. However, we haveshown that alternative models that are realis-tic about the needs and limitations in the field,and that take account of the different motiva-tions of the people involved, do work. By link-ing existing resources with user needs, we canencourage the development of crucial diag-nostic tools, for the benefit of developers andpatients alike. ■

Martine Usdin, Martine Guillerm and Pierre Chiracare with the MSF Campaign for Access to EssentialMedicines, 4 rue St Sabin, 75011 Paris, France.

1. Chappuis, F., Loutan, L., Simarro, P., Lejon, V. & Buscher, P.Clin. Microbiol. Rev. 18, 133–146 (2005).

2. Carter, R. & Mendis, K. N. Clin. Microbiol. Rev. 15, 564–594(2002).

3. Luxemburger, C. et al. Trans. R. Soc. Trop. Med. Hyg. 92,45–49 (1998).

4. O’Dempsey, T. J. et al. Trans. R. Soc. Trop. Med. Hyg. 87,662–665 (1993).

5. Project Selection, Decision Analysis and Profitability in thePharmaceutical Industry www.wma.net/e/publications/pdf/2001/senn.pdf

6. Piper, R. et al. Am. J. Trop. Med. Hyg. 60, 109–118 (1999).7. http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-95-

001.html

Malaria tests tailored for use in Africa.

“Large doses ofgoodwill andunlimited access to freezers are not enough.”

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