snippets of achievement · onchocercal skin disease is com-monly found, the beauty of the skin is...

Snippets of achievement

. . . T H E PA S T I L L U M I N AT I N G T H E F U T U R E . . .

UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR)


17 examples from the past illuminating the future

UNDP/World Bank/WHO Special Programme for Research

and Training in Tropical Diseases (TDR)

TDR/GEN/01.1

This document is not a formal publication of the World Health Organization (WHO), and all rights arereserved by the Organization.The document may, however, be freely reviewed, abstracted, reproduced ortranslated, in part or in whole, but not for sale or for use in conjunction with commercial purposes.

The views expressed in documents by named authors, are solely the responsibility of those authors.

© TDR 2001

Editor: Nina MattockConcept and design:Andy Crump and Lisa Schwarb

ForewordTDR’s new strategy represents an evolution of a very dynamic programme. It builds on 25 years ofsuccess in research and training in tropical diseases.The document at hand is an attempt to illustrate thestrategy by providing examples from the past. Theexamples have been selected to highlight TDR’s rangeof expertise, its global leadership in the field, andits unique capability for building and maintainingpartnerships, involving public and private sectors, anddeveloping and developed countries alike. For a fullaccount of achievements the reader is referred to theTDR biennial programme reports.The design and layout of the Snippets of Achievementwill hopefully appeal to a wide range of audiencesincluding more outside the circles of the Programme’susual stakeholders.

Carlos M. Morel, Director, TDR

Erik Blas, Programme Manager, TDR

Background TDR supports research to find solutions to public health problems related to neglected infectiousdiseases that affect poor and marginalized populations. The Programme specifically focuses on ten tropical diseases: malaria, tuberculosis, schistosomiasis, lymphatic filariasis, onchocerciasis, leish-maniasis, Chagas disease,African trypanosomiasis, leprosy, and dengue. Some of these diseases arethe targets for major global efforts of control. The others are also causing major public healthproblems and are targets for regional and national control efforts, as they affect different parts ofthe world in different ways, depending on social, economic, political, and ecological factors.Appropriate means for control often do not exist, are not accessible for those in need, or areincreasingly becoming ineffective, for example, due to drug resistance.A major determinant for the burden of disease is poverty. For the TDR group of diseases, the gapbetween the world's 20% poorest population groups and the 20% richest, in terms of death, iswide. If the world’s poor were to suffer the same death rates (from TDR diseases) as the world’srich, then the gl;obal number of deaths would be reduced markedly - by 97.5% from tuberculo-sis, by 99.6% from malaria, and by 99.9% from the other TDR diseases. Only diarrhoeal diseases,childhood cluster diseases, and maternal conditions come close to producing the same excessdeath amongst poor populations as do the TDR diseases.In addition to the direct suffering caused by tropical diseases, they also adversely affect the socioe-conomic development of poor countries and populations. For example, studies have shown thatin Kenya, 11% of primary school days are lost to malaria, with the disease also causing losses of2-6% of the nation’s GDP. In Nigeria, 1-5% of the country’s GDP is lost due to malaria. In thePhilippines, schistosomiasis infection causes annual losses of 41.6 workdays, compared to 3.8 lostdays in control groups.

StrategyTDR uses research to find solutions to public health problems related to neglected infectious dis-eases that affect the poor and disadvantaged.This requires not only close collaboration with dis-ease control programmes and ministries of health, but also with researchers and product devel-opers from industrialized and developing countries. It further requires strong technical and man-agerial systems and expertise, in addition to sufficient and reliable flows of appropriate resources.

Value-based organizationTDR is a value-based organization that draws its values from the international community.TDR’s specific organizational beliefs and values are:

• Good health is an essential foundation for social and economic development and access tobasic health care is a human right. “ The enjoyment of the highest attainable standard of healthis a fundamental human right.”

• Social, economic and gender inequities are major impediments to improvements in health status.

• Research and development of means to combat disease and improve health must adhere tointernationally accepted ethical principles.

• Knowledge is a crucial element in health improvement, and the attainment of self-reliance inresearch and development in disease endemic countries is key to sustainability.

• Closing of the global gap in research and product development between the rich and poorrequires collaboration and partnership between the public and private sectors and involvementof research, planning and implementing agencies at international, national and local levels as wellas the targeted populations.

• It is essential for the successful functioning of TDR that it retains scientific independence, oper-ational transparency and special programme status within the UN system.

• As an organization of the international community, TDR values professional competence,together with gender and geographical balance in staffing, committee membership, and partic-ipation in research and product development.

GoalsTDR contributes to the attainment of the following goals:

• To alleviate inequity and poverty and foster social and economic development in endemiccountries through reduction of mortality, morbidity and disability caused by neglected infectiousdiseases which affect poor and marginalized populations.

• To increase research self-reliance in endemic countries for identifying needs and developingsolutions to public health problems caused by neglected infectious diseases.

ObjectivesThe objectives are considered within TDR’s managerial control.Their attainment is the collectiveresponsibility of the whole Programme across diseases, functions, and categories of staff. Theattainment of the objectives is the basis on which the strategy will be reviewed and evaluated.

• To improve existing and develop new approaches for preventing, diagnosing, treating, and con-trolling neglected infectious diseases which are applicable, acceptable, and affordable by devel-oping endemic countries, which can be readily integrated into the health services of thesecountries, and which focus on the health problems of the poor.

• To strengthen the capacity of developing endemic countries to undertake the research requiredfor developing and implementing these new and improved disease control approaches.

In-house expertiseTDR has a full range of in-house scientific expertise, from basic biomedical and social science,through product development, to clinical field research, capacity building, and communication, etc.The breadth and depth of this expertise in the field of tropical diseases is unparalleled.TDR has a reputation for efficiency, stability, and transparency – it is a safe investment. The pro-gramme has developed and continues to strengthen its capacity to manage, in an efficient way, alarge number of projects which are implemented in partnerships with outside experts through-out the world.

A Special ProgrammeAs a special co-sponsored programme,TDR has the advantage of being housed within the UN sys-tem, while at the same time, donors and clients have direct managerial authority through the JointCoordinating Board.

How does TDR work and what does it produce?TDR acts as a catalyst by facilitating R&D agenda and priority setting, funding projects, and provid-ing service in the form of technical guidance, capacity building, and brokerage to bring partnerstogether who have the comparative advantages required to make the end-product become a real-ity. TDR is rarely the owner of the final product, nor is it normally the sole contributor to theprocess resulting in the product.That is, the products materialize through the joint efforts of manypartners, including academia, industry, public and private institutions, and donors from developing anddeveloped countries.TDR has a unique set of operational capabilities, which allows it to bring together the world’s lead-ing researchers and product developers from the public and private sectors, from developing anddeveloped countries, to address public health problems related to neglected infectious diseases.TDR’s end-users are the poor and marginalized populations in developing endemic countries whodo not have access to appropriate and cost-effective means to prevent and treat their neglectedinfectious diseases.TDR reaches the end-users through its clients in public and private health sys-tems and national and international disease control programmes.TDR’s end-products are solutions to public health problems.These will emerge from knowledge gen-erated by research, and from developing, testing, and validating tools, intervention methods, andimplementation strategies. The products will range from environmental, through population and sys-tems based interventions, to products aimed at diagnosing and treating diseases in the individual.These products must be applicable, acceptable, and affordable by developing endemic countries,easy to integrate into the health services of these countries, and must focus on the health prob-lems of the poor.

Expected Results The snippets of achievement in this document are organized according to the six technical expect-ed results areas of the strategy:

A. New basic knowledge

New basic knowledge about the biological, social, economic, health systems and behavioural deter-minants, and other factors of importance for effective control of neglected infectious diseases.

• Onchocercal skin disease

• The transformation of a mosquito

• Parasite genome

B. New and improved tools

New and improved tools for use in infectious disease prevention and control, e.g. drugs, vaccines,diagnostics, epidemiological tools, environmental tools, etc.

• Multidrug therapy for leprosy (MDT)

• New drugs brought to registration

• Rapid mapping for onchocerciasis

C. New and improved intervention methods

New and improved methods for applying existing and new tools at the clinic and community levels.

• Vector control for Chagas disease

• Bednets

• Unit-dose packaging of antimalarials

D. New and improved policies, prevention and control strategies

New and improved policies for large-scale implementation of existing and new prevention andcontrol strategies.

• Community-Directed Treatment (ComDT)

• Getting drugs into wide control use

E. Partnerships and capacity building

Building partnerships throughout the world and increasing the involvement of developing coun-try researchers and product developers by providing support for building research capacity.

• Partnerships in science

• Building research capacity in least developed countries

• Technology transfer

• Knowledge and research capacity for schistosomiasis control in China

F. Dissemination of information, guidelines, instruments and advice

Provide technical information and advice and publish research guidelines and instruments.

• Internet communication

• Guidelines to good practices


Examples from the past illuminating the future

Onchocerciasis, also known as riverblindness, hasplagued millions,especially in Africa,for centuries. Thecommon name portrays the commonperception of the disease and its publichealth impact – it causes severe eye problems includingpermanent blindness,and shortens lifeexpectancy by up to 15 years. But in 1990, anotherimpact of this diseasebecame known.

N E W B A S I C

Why did TDR become involved?

Onchocercal skin diseaseOnchocercal skin disease

Prior to 1990, the social implica-tions and cultural aspects of on-chocercal skin disease had beentotally neglected, especially wherewomen were concerned. For ex-ample, in areas of Africa whereonchocercal skin disease is com-monly found, the beauty of theskin is culturally and socially ex-tremely important, so the impactof the disease is exacerbated. In1989,TDR decided to take a com-pletely new approach and initiatework on the socioeconomic im-

pact of the skin disease. This hadnot been done before, and noother agency was working in thisfield. In its pioneering work, TDRbrought together social scientistsand biomedical scientists to beginexploring hitherto neglected as-pects of this disease.

IntroductionIn 1990, the devastating impact of the skin disease accom-panying infection was recognized and began to be quanti-fied. Onchocercal dermatitis causes a variety of problems,mainly as a result of the incessant and unbearable itchingthat arises from infection and leads to scratching, which inturn leads to bleeding and ulceration of the skin, and oftento secondary infection. Disfiguring skin lesions and alter-ations of skin pigmentation also arise, while rashes, jointand bone pain, headache and fatigue are commonplace. Thedisease causes lost work and productivity, and schoolchild-ren’s education suffers due to distraction in class caused bythe constant itching. It is estimated that 60% of disabilityadjusted life years (DALYs) lost due to onchocerciasis can beattributed to skin disease. In 1990, of an estimated 15 mil-lion people with onchocerciasis living in Africa, 8-9 millionlived in areas associated with severe skin disease and 6-7million in areas associated with blindness. Onchocercal dermatitis is now recognized as a major healthproblem. As well, it carries with it a severe social stigma,compounding the pain and suffering that those infectedwith the disease already have to live with.

K N O W L E D G E

TDR played a leading and uniquerole, opening the door for scien-tists, agencies and institutions toexamine and expose other as-pects and impacts of diseases be-yond the usual biomedical ones.TDR initiated and supportedstudies in communities to uncov-er the underlying feelings and

concerns of individuals regardingonchodermal dermatitis. Affectedpeople worried that the skin dis-ease had an effect on their abilityto interact socially, and otherscomplained of being afraid to dis-close their disease because theywere embarrassed by having con-tracted the disease and feared be-ing ostracized. Villagers were up-set by the intensive itching, andcited fatigue and insomnia as se-rious concerns, also revealing that1 in 3 of them were sufferingfrom low self-esteem problemsassociated with the disease andthe social isolation that resulted.A further 33% believed theywould never marry because ofthe social stigma surrounding thedisease, while 1-2% of the popu-lation had considered suicide as adirect result of onchocerciasis.Children were at least twice aslikely to drop out of school if the

head of their household sufferedfrom the illness.TDR galvanized governments,control programmes, other inter-national agencies including theTDR co-sponsors, researchersand public health workers. Itachieved this by mobilizing andpartially funding an internationalnetwork of researchers, institu-tions and donor agencies, mostlyengaging cross-disciplinary groupsthat had never previously workedtogether.The work pioneered by TDR isnow bearing fruit in many otherareas and diseases. For example,work is being carried out on thesocial stigma attached to infectionwith leprosy and lymphatic filaria-sis, and on a wide variety of psy-chosocial, socioeconomic and be-havioural aspects of TDR targetdiseases.

The impact of TDR’s work hasbeen immense. Firstly, the workvalidated the extent and severityof the skin disease problem,creating awareness of its scale andencouraging the involvement ofplayers from governmental,NGO, industrial, academic andother communities. It significantlychanged the perception and ac-tions of donor-driven agenciesand disease control activities.Moreover, the gender aspects and differences in how diseasesaffect people were brought to thefore. With the advent of the safeand effective drug, ivermectin,to treat onchocercal infection,

the scope for eliminating the disease became obvious. Thework on onchocerciasis skin dis-ease contributed to the ground-work for plans, by the African Pro-gramme for Onchocerciasis Control (APOC), to eliminate on-chocerciasis based on distributionof ivermectin. Furthermore, in-creased knowledge and aware-ness of onchocercal skin diseasehas made it easier for healthworkers to engage affected com-munities in the single-dose, annu-al treatment programmes, and gettheir commitment to carry outand pay for the treatment them-selves.

What were the results?

What was TDR’s role?

TDR’s interest in transformation of the malaria mosquitobegan in 1991, when the vision of a mosquito unable to transmit malariabegan to take shape.


TDR engaged global expertisefrom a variety of disciplines andstimulated debate on the poten-tial of transformed mosquitos. In1991, 36 specialists were brought

together by TDR, the WellcomeTrust and the MacArthur Foun-dation to discuss promising re-search lines in this new approachto mosquito control.

Genetically-manipulated mosquito larvae fluoresce when exposed to UV light.

TDR has a number of compara-tive advantages, when comparedwith other research funding agen-cies, which mean it is in a positionto orchestrate this visionarywork. One advantage is that TDRhas an international research net-work and a global vantage pointfrom which to identify unmet re-search needs and to plan and car-ry through international researchprogrammes which uniquely fillthose needs. TDR was able tobring the world’s best minds to


IntroductionTo date, the only effective control programmes for malariahave been based on control of its vector, the mosquito, butincreasing resistance to insecticides, combined with theircost and detrimental environmental impact, has led to thesearch for new ways of controlling the vector. In 1994, TDRset up the Strategic Research Molecular Entomology pro-gramme to develop new approaches to mosquito control.Using the powerful techniques of molecular biology, thelong-term goal is to replace mosquito vectors in the wildwith mosquito populations that are unable to transmitmalaria parasites.In 2000, a malaria transmitting species of mosquito wastransformed through the insertion of a gene which makesthem glow green when excited with ultraviolet light. Thisgreen fluorescence gene is used as a model gene and might,at a later stage, be replaced by genes which inhibit parasitedevelopment. The insertion of the green fluorescence genewas a breakthrough, although there is still a long way to go- a projected 10 years. Potentially the most problematic stephas yet to be overcome - driving transformed mosquitos, car-rying genes that prevent development of the malaria parasitein them, into wild populations of mosquitos, after carefulassessment of the risks and consequences of such an action.

bear on the problem of trans-forming the mosquito. Anotheradvantage is that, owing to its in-ternational backing and base,TDRhas the organizational and finan-

cial staying power to see long-term projects through to com-pletion. And transforming themosquito was projected to takeup to 20 years to achieve.

Transformation of a mosquitoTransformation of a mosquito

N E W B A S I C

Three main areas of researchwere established. Firstly, to iden-tify parasite-inhibiting genes, andkey molecules in mosquitos es-sential for continued develop-ment of the parasite.This will pro-vide potential target genes andmolecules that can be introducedinto receptive mosquito strains tomake them refractory to malaria.The second line of research wasto develop genetic and moleculartools needed to insert selected

genes into the mosquito genome,i.e. to transform the mosquito, aswas first achieved in 2000. Thethird goal was to develop mech-anisms for driving selected genesinto natural populations of mos-quitos, including identifying genesaffecting the mosquito’s choice ofhost (man or animal).TDR mobilized a broad range ofscientists working in relevant fieldsof genetics, biochemistry and mo-lecular biology, inviting them to be

partners of international net-works. Over 100 projects in 19countries have been supported.This collaboration and open in-formation exchange producedexcellent results, confirming thefeasibility of this innovative ap-proach to malaria control.

Although it was known that theultimate goals would take at least10-20 years to fully realize, the in-termediate results, the scientificadvances, are significant and rele-vant and proving of immediatepractical use in areas such as tax-onomy and epidemiology. Someof the results so far are describedbelow.In understanding the molecularbasis of mosquito resistance tothe malaria parasite, major geneloci have been identified wheregenes responsible for disruptingparasite development in themosquito are located (thesegenes later to be transferred tosusceptible mosquitos).The factorresponsible, in susceptible mos-quitos, for activating the gametes,an early stage of the parasites lifecycle, was discovered to be xan-thurenic acid. A number of possi-ble receptors, such as enzymes,on the surfaces of mosquito cells,that the parasite recognizes be-fore it invades the cell, have beendistinguished. A new cell type –Ross cells – was discovered whichthe parasite ookinete stageprefers to invade after crossingthe midgut wall. More than 20 im-mune response genes (proteases,

protease inhibitors, transcriptionfactors) have been documentedfrom Anopheles gambiae mosqui-tos. An international effort inAnopheles genomics research hasbeen initiated (in 2000) as a newtool for improved understandingand control of malaria parasitedevelopment in the mosquito.In developing genetic and molec-ular tools for engineering a mos-quito that is resistant to malaria,the genetic transformation sys-tem described in 2000 was forAnopheles stephensi, one of themajor carriers of malaria in urbanareas of the Indian subcontinent.Use of this system, and its appli-cation to the main vector of hu-man malaria in Africa, An. gambi-ae, will speed up understanding ofthe physiology of the mosquitocarriers of the disease and theirinteraction with the malaria para-site, and could lead, ultimately, tothe replacement of wild mosqui-to populations with strains ofmosquito that cannot transmitmalaria.In order to develop methods tospread selected genes in wildmosquito populations, scientistsare developing a thorough un-derstanding of mosquito popula-

tion dynamics, and mosquitohost-finding behaviour. Possibledriving forces have been de-scribed (e.g. ability of transpos-able elements to spread throughnatural populations). New fielddata on the population structureof An. gambiae, from studies look-ing at the amount of genetic vari-ation between populations, indi-cate the existence of a historicalor present-day barrier to geneflow of this species, the major vec-tor in Africa. These data are im-portant for introducing andspreading foreign genes into wildvector populations. Throughcross-breeding of man-bitingspecies with animal-biting speciesof mosquito, proteins and genesthought to be involved in recog-nizing human odours have beenidentified, and cloning and initialcharacterization of several classesof these olfactory genes in An.gambiae have been performed.Of course, numerous and impor-tant scientific, ethical, safety andregulatory issues will have to beaddressed before such a strategycould be used to control a vec-tor-borne disease.


K N O W L E D G E

Despite the advancesof modern medicine,the chronic illness, disfigurement anddeath that can resultfrom parasitic infection still threatenthe majority of theglobal population and retard economicdevelopment.


Widespread and improper use ofthe few treatments and vectorcontrol measures that were oncecheap, effective, and easy to ad-minister, has resulted in the ap-pearance and spread of resistantparasites and vectors. Even wheredrug resistance is not yet a seri-ous problem, available treatmentsmay require long-term drug ad-ministration and/or hospitaliza-tion, involve regimens that havenot been standardized, or usecompounds that are sub-curativeor invoke severe side-effects. Inthe long term, vaccines are likelyto make a major impact butprogress is impeded by factorssuch as antigenic switching, muta-

tion, diversity, autoimmune stimu-lation and poor antigenicity, suchthat no vaccine is yet available forany parasitic disease.Rationally designed strategies,based on an understanding of:how parasites develop, survive,and reproduce in their differenthosts; parasite-host and parasite-immune system interactions; andfactors that determine behaviour,pathogenicity, drug resistance andantigenic variation, represent theonly practical approach to identi-fying new therapies. Sequencingand understanding those parts ofthe genome that encode this in-formation are key to develop-ment of the strategies. However,

most large-scale biotechnologyinitiatives involving sequencingand mapping are conceived andled by scientists in developedcountries.TDR represents one ofthe few opportunities for scien-tists from disease endemic coun-tries to participate and collabo-rate in long-term, far-reachingprojects and to acquire the ex-pertise necessary to exploit ad-vances in biotechnology.

IntroductionFor most parasitic diseases, current therapy often leavesmuch to be desired in terms of administration, regimen, tox-icity, and effectiveness. Potential vaccines are a long wayfrom market. Our best prospects for identifying new targetsfor drugs, vaccines, and diagnostics, and for dissecting thebiological basis of drug resistance, antigenic diversity, infec-tivity and pathology, lie in analysing and understanding theparasite genomes. International genome mapping, sequenc-ing and gene discovery initiatives are under way for a vari-ety of protozoan and helminth parasites.TDR has played an important role in the generation of knowl-edge about the genomes of the parasites that cause Africantrypanosomiasis, Chagas disease, leishmaniasis, schistoso-miasis, and lymphatic filariasis, and is now focusing on pro-viding capacity to utilize the parasite genome data and onsupporting developments in applied genomics and bioinfor-matics.

Parasite genomeParasite genome

N E W B A S I C

Genome projects break themould of conventional scientificpractice by being collaborative ef-forts performed with a servicefunction in mind and with thewish to disseminate data as wide-ly as possible. As an international-ly recognized lead organization intropical disease research, TDRwas in a unique situation to facil-itate and support the creation ofinternational collaborative net-works.TDR's unique position pro-vided an umbrella for conveninginternational experts and givingscientists from disease endemiccountries the opportunity to par-ticipate. The Special Programmestatus of TDR also provided theopportunity for developing part-nerships with other agencies andinstitutions to facilitate making theinformation available in publicdatabases. TDR's convening posi-tion also facilitated a forum forpresentation and discussion of

progress reports - a model thathas become standard procedurefor consortium approaches ingenome projects.As the work progresses and en-ters into the next phase – thepost-genomic phase - TDR’s rolewill increasingly be to strengthenthe capability of researchers fromdisease endemic countries and in-volve them in collaboration withthe genome networks in order toexploit the data generated by thegenome projects in developingnew tools for managing the dis-eases. TDR efforts will now focuson facilitating the acquisition ofexpertise in bioinformatics andapplied genomics by diseases en-demic country scientists. TDR'scontinued support for thegenome networks makes it pos-sible to organize internationaltraining programmes for transferand impact of these technologiesin disease endemic countries.

Parasite genome discovery hasbeen hugely successful and hasresulted in a logarithmic increasein the catalogue of known para-site sequences. The parasitegenome projects are generatinglarge amounts of data in diverseforms.These data are of wide in-terest as they pertain to groupsof organisms that are traditional-ly under-researched. All the para-site genome databases are in thepublic domain, available boththrough the Internet and for lo-cal installation. Therefore, ‘post-genomic’ investigations that ex-ploit the databases for functional

analysis provide ideal opportuni-ties for researchers from diseaseendemic countries to be at thecutting edge in this field of re-search, without being disadvan-taged by poor infrastructures.Thecoming years are likely to seehuge improvements in technolo-gy that will transform molecularbiology from an analytical scienceinto a discipline of structure andfunctional analysis, and into apowerful resource for in vivo ma-nipulation in order to identifynew targets for the developmentof diagnostics tests, drugs andvaccines.


TDR’s role

“The Schistosoma, Brugia malayi

(as model filarial nematode),

Trypanosoma brucei, T. cruzi and

Leishmania initiatives fall within

the UNDP/World Bank/WHO Special

Programme for Research and

Training in Tropical Diseases. TDR

resources are extremely limited

and its funding is largely ‘pump-

priming’ to facilitate development

of resources, strategies and

collaborations to support applica-

tions to national or international

agencies for larger-scale projects.

This ‘pump-priming’ is beginning

to bear fruit, with the Leishmania

and T. brucei genome initiatives

recently attracting multi-million

dollar support”1

Parasite genome initiative web sites:Leishmania network:www.ebi.ac.uk/parasites/leish.htmlTrypanosoma brucei network: parsun1.path.com.ac.uk/Trypanosoma cruzi network:www.dbbm.fiocruz.br/genome/tcruzi.htmlSchistosoma genome network:www.nhm.ac.uk/hosted_sites/schisto/Filarial network:helios.bto.ed.ac.uk/mbx/fgn/filgen1.html

Coordinating sitesParasite genome:www.ebi.ac.uk/parasites/parasite-genome.htmlWHO-TDR parasite genome committee: www.who.ch/tdr/workplan/genome.htmlParasite genome mailing listarchive: www.mailbase.ac.uk/lists-p-t/parasite-genome

K N O W L E D G E

A researcher inBombay who inter-viewed women on whatthey considered to bethe most difficult partof coping with leprosy,found that ‘it wastouch more than anything, that womenlonged for, and the loss of this intimateright symbolized such isolation and rejection.’


When TDR was founded in 1975,it took a leading role in leprosyresearch, strongly based on thepromises offered by molecular bi-ology, especially with a view toproviding new control tools. Bythe early 1970s, drug treatmentswere becoming ineffective. Ther-apy with the cheap and readily-available drug dapsone was inter-minably long and drug resistancewas becoming increasingly evi-dent. Leprosy therapy meant

years of continuous treatment, of-ten for life, and relapses were acontinual threat. Of the otherdrugs used, clofazimine couldcause dark discoloration of theskin, thus increasing the severetrauma of those who already hadto live with the unbearable socialstigma and sense of isolation thatleprosy induces. Another drug, ri-fampicin, already used extensivelyin the treatment of tuberculosis,had rapid bactericidal effect on

Mycobacterium leprae (the mi-croorganism which causes lep-rosy) but was extremely expen-sive and produced adverse side-effects. Even as the programmewas being established, TDR’sfounders recognized the failure ofmono-therapy and set the two-fold goal of improving drug effec-tiveness and reducing the dura-tion of drug treatments.

IntroductionLeprosy can be traced back at least 2500 years, making itone of the oldest recorded diseases afflicting humans. Achronic disease caused by a bacillus, which can be transmit-ted via droplets from the nose and mouth of infected peo-ple, it affects the skin and can cause nerve damage, eventu-ally leading to hideous deformities. It has struck fear andloathing in the hearts of communities down through theages, with millions being cast out, banished to lepercolonies, often disowned by their own families and lovedones. Poverty is a significant factor in preventing control ofthis dreaded disease. Ignorance of the disease has alsoplayed a major role. However, administering a cocktail of dif-ferent drugs in specific dosages – multidrug therapy, or MDT– can cure leprosy and should lead to its elimination.

MDT for leprosyMDT for leprosy

N E W A N D

In close collaboration with theWHO leprosy programme, TDRorchestrated and funded work onleprosy drugs, mapping dapsoneresistance (a long and arduousprocess) to establish the scale ofthe problem. TDR worked withresearch groups, scientists, nation-al leprosy programmes andNGOs, coordinating large-scaledrug combination trials in Indiaand Africa and seeing them

through to completion. As an in-dependent and trusted broker,TDR could organize and overseefield trials in disease-endemiccountries. It could also persuadepharmaceutical companies to en-gage in trials of their drugs along-side those from other manufac-turers, stimulate and engage sci-entists, researchers and govern-ments. And it could provide fi-nance and mobilize further re-

sources, following through onproducts that may not provecommercially profitable.The work revealed that combina-tion therapy was extremely effec-tive and, in 1981, WHO recom-mended the use of multidrugtherapy (MDT) for the treatmentof leprosy, based primarily onTDR’s findings.TDR continued theresearch to both improve thedrug combinations being usedand reduce treatment durations,working closely with the WHOleprosy programme. This contin-ued commitment resulted in var-ious other drugs being investigat-ed, and the so-called ‘ROM’ com-binations (comprising rifampicin,ofloxacin and minocycline) weredeveloped and introduced as ‘re-fined products’ in 1997, some 16years after MDT had becomeWHO recommended therapy.Other new drug regimens are stillunder trial.The hope is to reduceMDT treatment duration toweeks, or possibly even to days.

The work of TDR and its partnershas brought huge returns. Drugcombinations produced a highlyeffective treatment strategy, andthe leprosy bacillus has not de-veloped any resistance to MDT.Since the introduction of MDT,there has been a dramatic reduc-tion in prevalence of leprosy, from5.4 million registered patients in1985 to around 0.75 million at thebeginning of 2000.The disease hasbeen eliminated from 98 coun-tries and the global leprosy elim-ination targets will be met in

2001. Early detection and treat-ment with MDT has preventedsome 3-4 million people from be-ing disabled. However, there is aneed to detect and treat about2.5 million new cases over thenext five years to achieve elimi-nation. The Japanese-based Nip-pon Foundation has played a lead-ing role in bringing the eliminationof leprosy closer to fruition, to-gether with the Novartis phar-maceutical company and Novar-tis Foundation for Sustainable De-velopment, which has also made

a major contribution in providingMDT free of charge to all leprosypatients.Along with TDR, they arecrucial players in ensuring that re-search on the transmission and in-cidence of leprosy, on improvedmethods of detection and on pre-vention and management ofnerve damage, continues and thatMDT is widely employed to attainthe goal of eliminating leprosy andridding the world of one of itsmost dreaded diseases.



2

4

6

8

10

12

Prevalence Cured with MDT

1985 86 87 88 89 90 91 92 93 94 95 96 97 98 99 2000

Global impact of MDT on Leprosy(in millions from 1985 to 2000)

I M P R O V E D T O O L S

According to an analysis by Pécoul et. al.1 of the 1233 newdrugs identified asreaching the marketbetween 1975-97, only13 were approvedspecifically for tropicaldiseases. Of these 13, six were developed withTDR support.

TDR’s role can begin anywherebetween the discovery of a newtherapeutic target for compoundidentification and the last stages of

its clinical development and reg-istration.TDR brings partners to-gether, providing strategic fundingand technical support, and organ-

TDR’s end-products are solutionsto public health problems causedby neglected infectious diseasesaffecting poor and marginalizedpopulations. Drugs constitutemany of these solutions – drugsare the mainstay of most publichealth programmes aimed at re-ducing mortality and morbidity inthe developing world.The centrepiece of TDR’s opera-tional capability is its ability tobring together the public and pri-vate sectors, industry and acade-mia, developed and developingcountries, in partnerships that


IntroductionThe problem is market failure. Drug research and develop-ment is so costly in terms of time and money, that, in theface of counterfeit drugs and circumvention of patent rightsin some countries, together with non-solvent populations,there are no market incentives to motivate the pharmaceu-tical industry. Unless commercial returns will be good and/orrisks reduced, the industry (with few exceptions) will notinvest time and resources in drugs for tropical diseases. Six of the 13 drugs identified by Pécoul et. al. – artemether,mefloquine, eflornithine, albendazole, ivermectin, and lipidassociated amphotericin – were developed with TDR help.Other drugs which have received TDR input and are now reg-istered for use include: mefloquine + pyrimethamine combi-nation, and artemotil for malaria. Also, TDR supported trialsof benznidazole for early chronic Chagas disease, praziquan-tel combinations for schistosomiasis, and albendazole combinations for lymphatic filariasis. In total, TDR hashelped bring 13 new chemical entities to registration or rec-ommendation for use in the control of tropical diseases, andothers are in the pipeline.

exploit the comparative advan-tages of each partner. By doing so,both the costs and the risks in-volved can be significantly re-duced and the relevance of theoutcome ensured. TDR not onlyprovides direct funding, but also

facilitates transfer of knowledgeand technology, and provides di-rect technical support to allstages of the processes involvedin bringing new drugs to registra-tion or recommendation for usefor disease control programmes.

New drugs brought to registrationNew drugs brought to registration


N E W A N D

Artemether is now registeredin over 30 endemic countries forintramuscular injection in treat-ment of severe malaria.Artemether can be recom-mended for treatment of schisto-somiasis in areas where there isno regular transmission of malar-ia (e.g. north of the Sahara andparts of the Middle East).Lymphatic filariasis has been tar-geted for elimination by 2020.The key strategy is mass treat-ment with a single, annual dose oftwo-drug treatment: DEC plus al-bendazole, or ivermectin plus albendazole.

Eflornithine is licensed for usein sleeping sickness in the US, Eu-rope, and 12 African countries.Treatment of children in the ear-ly chronic phase of Chagas dis-ease with Benznidazole has be-come common practice through-out Latin America and guidelinesfor clinical management havebeen published.Not only has TDR’s work led tomaking these drugs available foruse in disease control, the workhas also resulted in TDR, over theyears, being able to refine and fur-ther develop its strong and cus-tomized managerial systems and

expand its global network of re-searchers and developers capableof addressing all the aspects ofR&D required to bring new drugsfrom the earliest stages of dis-covery through to registration.TDR is a leading partnershipbuilder in this field.Several new organizations arenow trying to replicate the mod-els developed by TDR, particular-ly in relation to building partner-ships between the public and pri-vate sectors.


izing small and large-scale field tri-als in endemic countries followingstandards and regulatory require-ments compatible with registra-tion in developed countries. Someexamples are:Artemether, a derivative ofartemisinin, discovered and devel-oped by Chinese scientists, formalaria. In partnership withRhône-Poulenc Rorer,TDR spon-sored, coordinated and providedtechnical support for clinical trialsof artemether injection, and fur-ther development of regulatorydata for its use in malaria.Also, since the early 1990s,evidence for prophylactic effectsof artemether on juvenile formsof various species of schistosomehas been accumulating. Studies byTDR and its partners have shownthat this drug could play a role inbreaking the transmission of schis-tosomiasis in certain areas (whereit has already been very much re-duced, but final eradication hasproved difficult, e.g. Saudi Arabia,Morocco) and in control in cer-tain areas (e.g. Egypt).

Ivermectin, was originally dis-covered and developed by Merck& Co. Inc. for use in animals, butlater, TDR provided substantial financial resources and technicalinput for multi-country trialsagainst onchocerciasis. Ivermectinis the major tool for treatmentand control of onchocerciasis.More recently, TDR-sponsoredstudies demonstrated that iver-mectin used in combination withAlbendazole in annual, singledoses, is effective for the controlof lymphatic filariasis in Africa.TDR also supported studies thatdemonstrated albendazole, toge-her with diethylcarbamazine(DEC), to be effective for the con-trol of lymphatic filariasis in therest of the world. In the case ofalbendazole, the industrial partneris Smith-Kline Beecham (nowGlaxoSmithKline).Eflornithine for African tr y-panosomiasis was discoveredthrough basic science (it was orig-inally developed by Hoechst Mar-ion Roussel for treatment of can-cer, but proved to be of little use

in the clinic). A TDR-supportedstudy of metabolic pathways intrypanosomes led to the demon-stration, in mice, that eflornithinewas effective against the enzymeornithine decarboxylase, a key en-zyme in the multiplication of try-panosomes. TDR supported thework which led to registration ofeflornithine for use in sleepingsickness in 1990. But, eflornithineis expensive to produce so TDRfunded studies to find a new routeof synthesis, although these havenot yet borne fruit. Hoechst Marion Roussel (now Aventis)granted a licence to produceeflornithine to WHO, which isworking with MSF to identify newmanufacturers.Benznidazole for Chagas dis-ease.TDR/backed studies showedthat treatment of children in theearly chronic phase of Chagas dis-ease with benznidazole, to stopthe disease evolving to irre-versible cardiac lesions, is effec-tive. (Benznidazole was previous-ly only used in the acute phase ofChagas disease).


When ivermectinbecame available for the treatment ofonchocerciasis, and its potential for masstreatment becameapparent, 85% of theinfected populationlived outside the rangeof the OnchocerciasisControl Programme inWest Africa (OCP).


In anticipation of the need forrapid tools for identifying com-munities endemic for onchocer-ciasis, TDR had developed andfield tested methods for rapidcommunity diagnosis of on-chocerciasis using palpation foronchocercal nodules in a sampleof 50 adults. But TDR’s involve-ment in research on rapid map-ping followed from a specific re-

quest from the field. The key ac-tors in onchocerciasis controloutside the OCP area at that timewere a group of internationalnon-governmental developmentorganizations (NGDOs) workingin blindness prevention.They hadestablished a coordinating groupwith its secretariat in the WHOProgramme for the Prevention ofBlindness. The NGDOs wanted

to distribute ivermectin, but werefaced with the huge problem ofhow to identify which communi-ties to treat. The coordinatinggroup identified the need for ameans for rapid mapping and,knowing TDR to be involved inresearch on rapid assessment ofonchocerciasis, they turned to theProgramme for help.

IntroductionIn OCP countries, control was based on tackling of the black-fly vector through aerial spraying of insecticides over itsbreeding sites in fast-flowing rivers. The advent of iver-mectin presented a tool which could be used as the mainstrategy for control in the remaining endemic areas not suit-able for the OCP type of vector control. However, at firstthere was a huge bottleneck because it was not known onwhich areas and communities ivermectin treatment shouldbe focused. It was necessary to first determine the geo-graphical distribution of the disease across countries orregions, and identify the particular communities to treat,before control programmes based on mass treatment couldbegin. Thus, TDR helped develop a new tool to rapidly assessthe onchocerciasis situation – rapid epidemiological map-ping of onchocerciasis (REMO). Using REMO, it is possible to assess quickly and cheaplywhich communities are at high risk and where they are locat-ed. Basically, REMO works by using geographical information,particularly the presence of river basins, to identify commu-nities likely to be at high-risk. A sample of these high riskcommunities is then assessed rapidly for the prevalence ofonchocerciasis (by feeling for onchocercal-worm-containignodules in 50 adults per village).

Rapid mapping foronchocerciasisRapid mapping for onchocerciasis

N E W A N D

In developing REMO,TDR built onthe experiences of the On-chocerciasis Control Programme(OCP), whose detailed mappingof onchocerciasis had led to un-derstanding of the spatial distri-bution of the disease, particularlyits relationship with river basinsand potential blackfly breedingsites. TDR’s role in developing REMO was catalytic and veryproactive. It brought everyone to-gether and got the process start-ed. The need for REMO camefrom the field, but development ofthe method was driven from in-side TDR.At that time,APOC hadnot been established, althoughsubsequently TDR was to workclosely with this body. TDR alsoworked closely within WHO withHealthMap, to develop a geo-graphical information system(GIS) for analysis of the on-chocerciasis data.After developing REMO,TDR wasinvolved in further standardizingthe tool in conjunction with on-chocerciasis control personnel.The REMO manual was devel-

oped in several stages – an earli-er edition was produced after theinitial trial in Cameroon, whichwas later revised after a majorworkshop in Nigeria, where firstapplication of the tool on a na-tional scale was planned. Guide-lines for analysis of REMO resultswere subsequently developed to help onchocerciasis controlpersonnel interpret results fromREMO and use them to identify

priority areas for mass treatment.TDR also carried out the first im-plementation of REMO, its firstlarge-scale application, underfunding from the World Bank.Several countries were complete-ly mapped, including Nigeria,Cameroon, Tanzania and Uganda.Fur ther implementat ion of REMO was taken over by APOCin 1996, after establishment of thisProgramme.

REMO has become a key tool in the control of onchocerciasisand is used to provide basic in-formation for rational planning of large-scale ivermectin treat-ment in APOC countries. Com-

plete country maps, targeting theareas for treatment, are available.Integration of REMO results in aGIS, overlapping the onchocerci-asis map with a population map,allows control programmes to

plan which communities to treatand obtain better estimates of thenumber to be treated and thenumber infected, as well as a bet-ter estimate of the burden of thisdisease.



No REMO yet

No CDTI

CDTI unlikely (to refine)

Definite CDTI areas

CDTI likely (to refine)

Source: NOTF Nigeria, June 1998Prepared by WHO/UNICEF HealthMapfor APOC


Chagas disease, caused by the parasiteTrypanosoma cruzi,exists only on theAmerican continent,where it is endemic in18 countries of Centraland South America.In the whole of LatinAmerica in 1991, an estimated 16-18 million peoplewere infected andanother 100 millionpeople were at risk of becoming infected.


In 1977,TDR’s Scientific WorkingGroup on Chagas Disease identi-fied several urgent needs: devel-opment of new drugs; improvedmethods to eliminate the parasitefrom blood banks; better diag-nostic testing; improved vectorcontrol methods. There was em-phasis on gaining better under-standing of the geographical dis-

tribution, prevalence and clinicalvarieties of Chagas disease and ofthe distribution of its vectors.By the early 1980s, it was recog-nized that the only feasible meansof controlling Chagas disease wasthrough attacking the insect vec-tor with insecticides. Housing im-provements were seen as a com-plementary viable option.

IntroductionSome 45 000 deaths occur annually from Chagas disease. Thedisease is difficult to diagnose in its early stages, with mostinfected people not exhibiting any significant clinical symp-toms. However, some 45% of infected individuals move on tothe chronic stage, with irreversible damage to the cardiac,digestive or neurological tissues, for which no treatment isavailable. The disease usually afflicts people in rural areas and thoseliving in poor communities where houses are built from verybasic materials. Roofs are generally made of dried straw withmud-plastered walls, providing a haven for the bloodsuckingtriatomine bugs which transmit the disease to humans. Inrecent years, the disease has also become a concern in urbanareas as well, when people migrate into the cities with theparasite already in their bloodstream. Here, the disease istransmitted via blood transfusions. Canisters, which release pyrethroid insecticidal fumes whenlit, have been developed and deployed in the fight againstChagas disease since the 1980s. They are designed for use byhouseholders themselves. TDR also supported the develop-ment of insecticidal paints, for use by spray teams. Thesepaints retain their insecticidal activity longer than tradi-tional sprays.

Vector control forChagas diseaseVector control forChagas disease

N E W A N D I M P R O V E D

Along with regional organizationsand bilateral agencies,TDR playeda crucial role in helping mobilizeresources at the global level to fi-nance research on Chagas dis-ease, and in international coordi-nation and linking of researchers,particularly those in endemiccountries, but also those in NorthAmerica and Europe. The resultwas the establishment of a net-work of national institutions,working in collaboration withgovernment control programmes.Scientists at the Centro de Inves-tigaciones de Plagas e Insecticidas(CIPEIN) began collaborationwith TDR in 1978. TDR funded

development of the canistersfrom 1980, organized and part-funded multicountry studies ofthe new vector control tools (in-secticidal paints and fumigant can-isters), and helped establish astandard protocol to evaluate thestudies. In most countries, thepaints were shown to reducerates of house infestation by a fac-tor of 2-3 compared with con-ventional spraying and to providean improved living environment.The canisters, which are now pro-duced and marketed by local in-dustries, are employed optimallyto maintain insecticide levels in-side houses.

Argentina, Bolivia, Brazil, Chile,Paraguay and Uruguay began the‘Initiative for the Elimination ofChagas Disease by SouthernCone Countries’ in 1991, usingfumigant canisters as one of thetools to achieve this goal.In the Southern Cone nations,house infestation with triatominevectors fell by up to 90% be-tween 1982 and 1994. Diseasetransmission by vectors andblood transfusion has now beenhalted in Uruguay, Chile andBrazil. Interruption of transmis-sion in Argentina, Bolivia andParaguay is expected by 2003.The fumigant canister is now al-so being evaluated to fight an-other disease vector, the mosqui-to Aedes aegypti, which transmitsthe virus causing Dengue.



PARTNERS

(fumigant canisters)

• Ministry of Health(Argentina)

• National Research Council(Argentina)

• CHEMOTECHNICA, SA(Argentina)

I N T E R V E N T I O N M E T H O D S

Trials have shown that the use ofinsecticide- treated nets protect sleepingchildren from beingbitten by mosquito vectors, resulting indramatic reductions in deaths among children under five.

Why did TDR get involved?

TDR’s played various role, actingas a forum for ensuring that treat-ed nets get taken more seriouslyin the prevention of malaria, pro-viding evidence of their efficacy.TDR also helped to work outstrategies, along with WHO, forproduct development and waysof sustaining access to nets incommunities.Another role was to stimulate theprivate sector – the pesticide pro-ducers – to develop formulationsand packaging adapted for hometreatment of nets. Dip-it-yourselfkits were designed, along with ainstructions for safe and effectiveuse of the kits, including where lit-eracy is low.The instructions werewell tested in urban and rural

communities and illiteracy wasnot found to be a problem, al-though at the outset, the idea ofa dip-it-yourself kit for use in de-veloping countries had been re-garded with scepticism by mostpeople, including public health au-thorities and chemical manufac-turers.TDR also answered misgiv-ings about the use of nets. Oneconcern was that use of the netswould induce pyrethroid resist-ance in the mosquito population.But TDR studies indicated that,even in areas where there is suchresistance, treated nets remain ef-fective, and their use is unlikely toinduce resistance in malaria vec-tors. Another concern was thatuse of treated nets in hyper-

TDR became involved because ofits comparative advantage in see-ing large-scale field trials throughto completion. This is due to itsorganizational and financial stayingpower made possible by its inter-national backing and base. TheTDR trials were the largest trialswith nets ever carried out, involv-ing altogether almost half a millionpeople, 20 research institutes anddonors.They were carried out indifferent epidemiological settingswith different malaria risks.


IntroductionTreating nets with a biodegradable pyrethroid insecticide hasadded to their efficacy. The first TDR studies in 1990-91, inthe Gambia, showed a reduction of 63% in mortality from allcauses in children between the ages of one and five who hadslept under treated nets. Later trials in other countriesshowed lesser, but still significant, reductions in mortality –of 33% in the Kenyan trials and 17% in the Ghanaian trials.In the Kenyan trials, the nets not only prevented deaths butalso led to a 40% reduction in hospital admissions for severemalaria, indicating that their use could reduce the burden onhealth services. The results of the trials suggested that some500 000 African children might be saved each year frommalaria-related mortality if the nets were widely and proper-ly used. As well as demonstrating the efficacy of treatednets, TDR supported work to improve methods for their treat-ment with insecticide.

Insecticide treated netsInsecticide-treated nets


endemic malaria areas mightmerely shift the predominant ageof mortality to a higher age group– that as children may not be in-fected early in life, they will notdevelop partial immunity tomalaria, and so will succumb tothe disease later in life. Findings

from TDR-supported studies in-dicate that delaying infection isnot a problem.Insecticide treated nets provideone of the best malaria controlmeasures to date, and TDR oc-cupied a catalytic role to bring itall together.

The findings of the efficacy trialsemphasized that the contributionof malaria to child mortality inAfrica had been underestimatedand that potentially large benefitsare to be gained from malaria pre-ventive interventions.The demonstration of efficacy ofthe nets encouraged the privatesector to undertake product de-velopment and bring new innova-tions to the market (‘dip-it-your-self ’ kits; more durable nets; bed-nets that don’t need re-dipping).The first trials of treated bednets,in the Gambia in 1990-91,demonstrated their efficacy topublic health officials in the coun-try, who became aware that treat-ed nets are a very cost-effectivetool for fighting malaria, rankingwith some of the most efficienthealth interventions available (e.g.childhood immunizations). Afterthis, the Gambian government ini-tiated a country-wide programmefor the implementation of net im-pregnation in villages with primaryhealth care clinics.People’s attitudes to nets arechanging, with more and morehouseholds taking to them aspeople recognize that using netsis a way to save the lives of theirchildren.Today, the use of treated nets isan important part of the globalstrategy proposed by WHO toprevent people being infected by

vector mosquitos, and is one ofthe main strategies adopted byRoll Back Malaria.WHO’s Region-al Office for Africa asked for a‘phased and continuously moni-tored implementation of treatednets’. Overall, it is estimated that,at the present time, less than 5%of people at risk of malaria inAfrica, south of the Sahara, usenets. However, the figures rangewidely between different coun-tries:• In Nigeria, evidence shows that

less than 2% of the populationare aware of the effectivenessof treated nets while less than1% actually use them.

• In Tanzania, more than 70% ofhouseholds in Dar es Salaamand more than 20% of house-holds in many rural areas haveat least one net.

• In The Gambia (the only coun-try where nets are used on awide scale), over 76% of the ru-ral population have, and do use,nets.

• In Vietnam, the number of peo-ple protected by treated netsincreased from 300,000 in 1991to almost 10.8 million in 1998,although it is estimated that halfof the population of 75 millionis at risk of malaria.

Thus, TDR has helped prove theprinciple of efficacy of treatednets. But the challenge ahead isnot insignificant. With the goal for

African countries, under the RBMbanner, of 60% coverage of people at risk from malaria withnets by 2005, there will be muchcollaborative implementation re-search, including integration of in-secticide-treated net activitieswith other health interventionse.g. integrated management of thesick child and mother-and-childhealth.


PARTNERS

Funding partners: • United Nations Children’s

Fund (UNICEF) • United States Agency for

International Development(USAID)

• International DevelopmentResearch Centre (IDRC)

• Centers for Disease Control (CDC)

• Canadian InternationalDevelopment Agency(CIDA)

• Wellcome Trust• Save the Children Fund• London School of Hygiene

and Tropical Medicine• Italian Cooperation

Funded partners: Ministry of Health of: • Ghana • Tanzania • The Gambia • Kenya • Burkina Faso


Early diagnosis andprompt, effective treat-ment of malaria is akey strategy for malar-ia control.1 The rolethat home treatmentcan play in this strate-gy, especially forAfrica, became appar-ent after better under-standing of care seek-ing behaviour wasreached.


TDR’s role has been to identifypossible problems that might im-pact on the effectiveness of hometreatment, to urgently developand implement strategies to solvethese problems, and to provideconclusive evidence of the effec-

tiveness and impact of hometreatment on the malaria burden.In 1998, TDR constituted a taskforce of experts who took re-sponsibility for these activities andcommitted themselves to work-ing with multi-country, multi-disci-

TDR funded many of the studiesin treatment seeking behaviour2

that prompted the new strategyfor malaria control adopted bythe Roll Back Malaria initiative.Through the work of the varioustask forces in its Applied Field Re-search area, TDR had establisheda network of interested and ableteams in countries who could car-ry out the research.The initial ex-ploratory studies, formulatedmainly in the context of healthsector reforms, had identified po-tential interventions e.g. trainingof shopkeepers and vendors, unit-dose packaging of antimalarials toimprove compliance, improving

IntroductionThe majority of families treat their children at home usingantimalarials and/or antipyretics bought from drug vendorsand/or village shops as the first line of treatment. However,families often buy insufficient amounts, there is very littleinformation provided with the treatment, and even whenthey do receive the full course, compliance with treatmentrecommendations is poor. The tendency is to stop treatmentas soon as the symptoms disappear, saving any remainingtablets for future illness episodes. Despite these shortcom-ings, at the Abuja Summit in April 2000, the heads of stateof most African countries, in the context of Roll Back Malaria(RBM), committed themselves to ensuring that diagnosis and treatment of malaria is made available as peripherally aspossible, including home treatment, in an effort to makeappropriate treatment available and accessible to the poor-est groups in the community.


community awareness for earlyappropriate home treatment,prompt referral of severely ill chil-dren. These early, very localizedexperiences formed the corner-

stone of the home managementpackage of interventions that havebeen developed further and test-ed through multi-country studies.

Unit-dose antimalarial packsUnit-dose antimalarial packs


plinary teams to provide, withinfive years, the answers to the fol-lowing questions: Is it possible andfeasible to change the behaviourand practices of mothers, house-holds and communities in orderto increase the extent of early, ap-propriate care for childhood un-complicated fever episodes andreferral for severe illness in malar-ia endemic countries? If strategieswhich prove feasible and effectivein changing behaviour and prac-tice were to be implemented ona much wider scale, would theyhave an impact on morbidity andmortality?

Country teams (Ghana, Nigeria,Uganda, Burkina Faso) were se-lected on a competitive basis. Acommon framework was devel-oped and proposals were devel-oped along this framework. Fund-ing and technical support wasprovided to the teams.

To date, results have been ob-tained from the Burkina Faso tri-al. In Burkina Faso, researchers de-signed a strategy for prompt andadequate home treatment that in-cluded: re-training of health staffof the local health unit, informa-tion/sensitization meetings andtraining sessions for communitiesfrom all study villages, and makingavailable pre-packaged antimalari-al drugs containing a full course oftreatment through trained village volunteers. The drugs were pro-vided in four different colour coded simple packages for differ-ent age groups, following theBurkina Faso treatment guidelines(0-6 months, 7-11 months, 12-35months and 36-69 months), eachcontaining a full course of treat-ment and a label with pictoral in-structions on how to administerthe drugs.A village volunteer soldthe drugs at a price previouslyagreed with the local health man-

agement team, which was calcu-lated to allow for full recovery ofthe purchase costs and a 10% in-centive margin for the volunteer.Three hundred and seventy-fivevillages participated in the studyand at least one volunteer wastrained in each village. Fifty-six percent of the children that weretreated by the village volunteerscomplied with the treatment, in-cluding the correct duration.The rate of progression towardscomplicated malaria was lower inchildren who were treated withpre-packaged antimalarials (5.1%)than in those not treated withthese drugs (11.0%). The overallreduction of progression towardssevere disease among users ofpre-packaged treatment was53.6%. In the four target agegroups, the progression rate tosevere malaria varied between3% and 7.1% in children who re-ceived pre-packaged antimalarials,

and between 8.1% and 18.2% inthe control group.The feasibility, sustainability, costand effectiveness over time of thestrategy for home treatment ofmalaria have not yet beendemonstrated on a larger scale.This is a challenge for implemen-tation research.


PARTNERS

• National institutions and ministries of health

• USAID (US Agency for InternationalDevelopment)

• Roll Back Malaria• Wellcome Trust


Community DirectedTreatment (ComDT) is a new approach to drug delivery inwhich the communityis in charge of the planning and execution of treatmentof its own members.


Onchocerciasis is a major publichealth problem, caused by infec-tion with Onchocerca volvulus,which results in visual impairmentand blindness, severe skin diseaseand maddening itching. The dis-ease has been controlled in theWest African savanna by the On-chocerciasis Control Programmein West Africa (OCP). But in theother endemic areas, where morethan 80% of all infected peoplelive, OCP’s vector control strate-gy was not feasible and thesecountries were “left looking overthe fence”. This changed with theemergence of ivermectin as an ef-fective microfilaricide, its registra-tion for the treatment of on-

chocerciasis in 1987, the devel-opment and testing of a controlstrategy based on mass iver-mectin treatment, and the deci-sion by Merck & Co. Inc. to do-nate the drug (Mectizan ®) freeof charge for onchocerciasis con-trol for ‘as long as needed’.In spite of this breakthrough,large-scale ivermectin treatmenttook off only slowly, as it was difficult for the health services to provide the required annualround of mass treatment foronchocerciasis, a disease of thepoorest communities 'at the endof the track'.As a result, it was ini-tially only the OCP and a few in-ternational NGOs who could en-

sure large-scale ivermectin treat-ment, often using mobile teams.To eliminate onchocerciasis as apublic health problem, annualtreatment needs to be sustainedover a very long time. Several at-tempts were made, therefore, tointegrate ivermectin delivery inprimary health care, or to usecommunity-based approaches inthe many areas where health fa-cilities were absent or not func-tioning. As it was not at all clearhow effective these different ap-proaches were, TDR was re-quested to evaluate them with aview to developing improved de-livery methods that would be sus-tainable.

IntroductionIn ComDT, the community is empowered to take full respon-sibility for the drug delivery process, to collectively decidehow and when to do the treatment, and to ensure adequateimplementation and follow-up. A TDR multi-country studydemonstrated, in 1995, the effectiveness of ComDT for iver-mectin delivery. The method has subsequently been adoptedby all onchocerciasis endemic countries in Africa as the prin-cipal strategy for drug delivery in onchocerciasis control.Since then, ComDT has proven very effective in achieving thetreatment coverage required to eliminate onchocerciasis as apublic health problem, and in 2000, some 20 million peoplereceived ivermectin treatment through ComDT. A recentexternal evaluation of the African Programme forOnchocerciasis Control (APOC), which covers 16 endemiccountries in Africa, concluded that ‘ComDT has been a time-ly and innovative strategy ... and communities have beendeeply involved in their own health care on a massive scale... ComDT is a strategy which could be used as a model indeveloping other community-based programmes’.

Community-Directed TreatmentCommunity-Directed Treatment

N E W A N D I M P R O V E D P O L I C I E S , P R E V E N T I O N

In 1994, TDR launched a multi-country study involving eight mul-ti-disciplinary research teamsfrom five African countries toevaluate and further developmethods for community-basedivermectin delivery. Early in thestudy, the researchers discoveredthat there was little active com-munity involvement in the ‘com-munity-based’ approaches, andthat communities had virtually noinfluence on how treatment wasplanned and executed. But socialscientists on the teams noted thatthese same communities routine-

ly organize much more complextraditional community activitiesvery effectively. This led to theidea of community-directed treat-ment in which the community itself would be in charge of thedesign and implementation ofivermectin treatment. This con-cept was tested in the secondphase of the study through alarge randomized comparison in272 communities of true 'com-munity-directed' treatment ver-sus 'community-based' treatment(as designed for communities bycontrol programmes.)

It was clearly demonstrated thatComDT is feasible and effective.Communities could effectivelyplan and implement ivermectintreatment, and they achievedhigher treatment coverage if theywere empowered to design andimplement treatment their ownway. It was concluded thatComDT is likely to be sustainablebecause of the commitmentdemonstrated by communityleaders and community distribu-tors, the high degree of involve-ment of communities, and theirability to recognize problems withtheir distribution methods and ef-fectively modify them. On the ba-sis of TDR’s work, ComDT wasadopted by OCP as its ivermectindelivery strategy and it becamethe principal control strategy forthe APOC programme in 1996.The main objective of APOC isnow “to establish effective andself-sustainable community-di-

rected ivermectin treatmentthroughout the remaining en-demic areas in Africa.”The large-scale implementationof ComDT produced importantnew challenges and APOC re-quested TDR to help strengthenthe evidence base for ComDTand undertake research on criti-cal implementation problems.These included issues relating to the integration of ComDT inthe health services and the sus-tainability of ComDT after cessa-tion of APOC support. Follow-upstudies showed that, althoughhealth workers initially had a neg-ative attitude to active communi-ty involvement in drug delivery,their attitude became much morepositive after experience withComDT. Poor communicationand interaction between commu-nity members and health workerswas also common but researchshowed that local stakeholders

meetings of community repre-sentatives and health workerscould significantly improve thisand further enhance a positive at-titude of health workers. The current research focus is on theability of countries and health sys-tems to support ComDT afterAPOC/OCP and on the use ofComDT for multi-disease inter-ventions. The effectiveness ofComDT for the treatment of lym-phatic filariasis has already beendemonstrated in a multi-centrestudy in Africa. ComDT achievedcoverage of over 80%, as com-pared to 45% by the health services. In this study, the issue ofintegration was addressed fromthe start and ComDT was intro-duced to the communities by the health services themselves.ComDT is now also recom-mended for mass treatment forlymphatic filariasis elimination inAfrica.



A N D C O N T R O L S T R A T E G I E S

Very few new drugsfor tropical diseasesreach the market and, even if they do, there are hugeinequities in access to drugs between richand poor countries.


TDR has helped bring a numberof drugs into disease control use.Below are some examples:To expand the use ofartemether for disease controluse for malaria,TDR negotiated apreferential price for the publicsector with the manufacturer,Rhone-Poulenc Rorer Doma. Acollaborative agreement wasmade with this company wherebydata from TDR-funded non-clini-cal and clinical studies were ex-changed for the preferential price.The necessary safety and efficacydata were completed by themanufacturer.To bring ivermectin into diseasecontrol use for onchocerciasis,TDR negotiated with the interna-tional pharmaceutical manufactur-

er, Merck & Co. Inc., for the supplyof ivermectin, and with the On-chocerciasis Control Programme(OCP) for provision of advice onhow to distribute and monitor thedrug in Africa. Merck & Co. Inc.donated ivermectin for onchocer-ciasis for ‘as long as necessary’. Itprovided 92 million tablets in1999 alone through 29 countries.To bring albendazole into dis-ease control use for lymphatic fi-lariasis,TDR helped negotiate withthe manufacturer, Smith KlineBeecham (now GlaxoSmithKline),who pledged, in 1998, to donatealbendazole to WHO for ‘use bygovernments and other collabo-rating organizations until lymphat-ic filariasis is eliminated from theworld as a public health problem’.

Because, even though a new drugmay be available, i.e. has reachedthe market, it may not be acces-sible to those who need it, for avariety of reasons. For instance, itmay be expensive to produceand hence to buy, so poor andmarginalized populations whoneed it cannot afford to buy it.TDR, from its base within theUnited Nations system, its longhistory of partnership with in-dustry, the donor and developingcountry research and controlcommunities, is in a strong posi-tion to act as a broker betweenthe different stakeholders. Theaim is to make drugs accessibleto those who have the needs butnot the means to reach the drugsvia the usual market mechanisms.


IntroductionThe international pharmaceutical industry, with few excep-tions, has shown little interest in drugs for tropical diseasesdue to market and government failures and enormous incomedifferences. Lack of money, lack of drugs, poor quality andcounterfeit drugs, prohibitive cost, incorrect use due to lackof training or lack of information, all lead to inaccessibilityfor the poor. There is a need to develop field-based drugresearch to determine optimum utilization and remotivateresearch and development for new drugs for the developingworld, as TDR is attempting to do through forming partner-ships between the public and private sectors and betweenthe developed and developing worlds. This snippet high-lights some examples of how TDR has helped bring new drugsinto disease control use.

Getting drugs intowide control useGetting drugs into wide control use

N E W A N D I M P R O V E D P O L I C I E S , P R E V E N T I O N

In 1999, the use of artemetheras intramuscular injection fortreatment of severe malaria wasexpanded to more than 30 en-demic countries and the drug wasincluded (restricted use) in theWHO Model List of EssentialDrugs.Mass treatment of lymphatic filariasis consists of a single doseof two-drug treatment – of DEC plus albendazole, orivermectin plus albendazole.

This is the basis of the strategy forelimination of lymphatic filariasisby 2020. Since the programmewas initiated (2000), SmithKlineBeecham has provided 34 milliontablets of albendazole throughWHO. WHO/TDR facilitated the procurement of 115 milliontablets of DEC, and Merck andCo. Inc. provided ivermectin forthe Ghanaian, Nigerian and Tan-zanian lymphatic filariasis pro-grammes.

The search for potential manu-facturers of eflornithine hadled, by January 2001, to the iden-tification of eight companies.One of these had produced asample which was being chemi-cally analysed, in January 2001, tosee if it met purity specifications.By February 2001, firm plans forproduction and supply of eflor-nithine were in sight.


To bring eflornithine into dis-ease control use for the gambi-ense form of African trypanoso-miasis,TDR was involved in nego-tiations with the private and non-governmental sectors.This drug isvery expensive to produce, but isvery much needed, particularlywhere resistance to arsenicals hasbecome a problem. Eflornithine isnow no longer manufactured, butthe manufacturer, Hoechst Mari-on Roussel Inc., has grantedWHO reference right to produceeflornithine. This will allow tech-nology for production of the drugto be transferred to a third party,also in the private sector, who willmanufacture eflornithine.

Médecins sans Frontières (MSF), anon-governmental organizationthat has made great efforts tocontain Sleeping Sickness, helpedto search for the third party whowould manufacture eflornithine.Together, TDR and MSF ap-proached donors who, it washoped, would provide funds toguarantee production of eflor-nithine, initially for five years.

A N D C O N T R O L S T R A T E G I E S

TDR is a global leader in fosteringpartnerships that generate new knowl-edge about tropicaldiseases and in bring-ing researchersfrom developingdisease endemiccountries into the mainstream of research to findsolutions to the pub-lic health problemsrelated to TDR’s target diseases.


TDR has a role as catalyst, facili-tating the R&D agenda throughsetting priorities, funding projects,and bringing together partnerswho have the comparative ad-vantages required to make end-products become realities. TDRhas unique operational capabili-ties which allow it to bring to-gether the world’s leading re-searchers and product develop-ers, from both public and privatesectors and both developing anddeveloped countries.These capa-bilities allow TDR to fund andmanage, in an efficient, account-able, and transparent way, a largenumber of research and productdevelopment projects as well asthe knowledge and capacity theygenerate.

During the past decade,TDR en-gaged with 2631 new partners in124 different countries. Thesepartners were engaged directly toundertake research and develop-ment, build research capacity indeveloping countries, develop re-search tools, or to provide sup-port and technical advice.

TDR is a knowledge managementand network organization, whichmanages the generation and ap-plication of knowledge throughlinking and brokering the stake-holders and processes needed forfostering and applying new knowl-edge to effectively combat tropi-cal diseases.TDR also has the goalof strengthening capacity in dis-ease endemic countries to un-dertake the research required fordeveloping and implementingnew and improved disease con-trol approaches. TDR believesthat knowledge is a crucial ele-ment in health improvement, andthat the attainment of self-re-liance in research and develop-ment in disease endemic coun-tries is key to sustainability.


IntroductionToday there is an imbalance in generation of knowledge andresearch funding: only 10% of global research funding isspent on diseases or conditions that account for 90% of the

global disease burden (a situation known asthe ‘10/90 gap’). TDR is about closing thisgap. In addition to looking at the physicalproducts, e.g. drugs, tools, guidelines, it isin the scientific literature that the resultsof TDR efforts in capacity building andpromotion of research in disease endem-ic countries can be found.

Partnerships in sciencePartnerships in science

P A R T N E R S H I P S A N D

A Wellcome Trust study on in-ternational funding for malaria re-search in 1998 concluded that, ofsix major funding bodies and rel-ative to the financial investmentof each, TDR had the highestnumber of acknowledgementsper unit of investment, and over-all the most funding acknowl-edgements; and that, according tocitations to published papers,TDR’s performance was in linewith other top funding bodies. Inanother Wellcome Trust study onmalaria research capacity inAfrica,TDR came out top of thelist for all indicators used, includ-ing source of funding for Africanmalaria research laboratories, andmaster’s degree and PhD trainingfor African researchers.A Harvard University analysis revealed TDR to be the leadingfunding source for research onAfrican trypanosomiasis, leish-maniasis, leprosy, malaria and onchocerciasis, ranking secondfor Chagas disease, filariasis andschistosomiasis. More than 83%of TDR funded papers were cit-ed at least once, and frequently-cited papers were not confinedto authors from industrializedcountries – of the 24 most high-ly cited papers in all subject ar-eas, four were authored by peo-ple from developing countries.This is a significant percentage –some 16% – when considered inthe light of the well-known biasof English-speaking industrializedcountry journals towards authorsfrom industrialized countries(overall, less than 0.01% of arti-cles indexed in MedLine originat-ed in developing countries).


Frequency of funding acknowledgements citation in randomly selected papers (Michaud 1998)

TDR Other major Others Disease (% of total funders (% of total

papers) (top three) papers)

African trypanosomiasis 51 NIH (USA) 15

European Commission 15Wellcome Trust 9

Chagas disease 30 CONICET (Venezuela) 39FINEP (Brazil) 28NIH (USA) 15

Filariasis 27 ICMR (India) 38CNPq (Brazil) 8Edna McConnell Clark Foundation 5

Leishmaniasis 33 CNPq (Brazil) 32NIH (USA) 6

Leprosy 25 LEPRA (Malawi) 21NORAD (Norway) 14SIDA (Sweden) 8

Malaria 30 NIH (USA) 17Wellcome Trust 12USAID (USA) 11

Onchocerciasis 39 NIH (USA) 28European Commission 24Wellcome Trust 10

Schistosomiasis 22 European Commission 23Edna McConnell Clark Foundation 18CNPq (Brazil) 9

Note:CNPq, Conselho Nacional de Desenvolvimento Científico e Technológico;CONICET, Consejo Nacional de Investigaciones Científicas y Technológicas;FINEP, Financiadora de Estudos e Projetos; ICMR, Indian Council of Medical Research; LEPRA, Leprosy Relief Association Control Project; NIH,National Institutes of Health; NORAD, Norwegian Agency for InternationalDevelopment; SIDA, Swedish International Development CooperationAgency; USAID, United States Agency for International Development.

C A P A C I T Y B U I L D I N G


Closing the global gap in researchand product development be-tween the rich and the poor, andincreased involvement of re-searchers from developing coun-

tries, are derived from the corevalues on which TDR is founded.One of the two goals of the Pro-gramme is to increase self-re-liance in endemic countries for

identifying needs and developingsolutions to the public healthproblems caused by neglected in-fectious diseases that affect them.Building research capacity has

IntroductionStudies have shown that up to 30% of African scientists arelost to the brain drain. The brain drain not only has severeimplications for the ability to build and maintain a criticalmass of tacit knowledge and skills in these countries, it alsomeans less research being done that is relevant to the prob-lems of the least developed countries. A major contributingfactor is the limited opportunities, after training, to conductmeaningful research as national research funding is extreme-ly scarce and international funding is often biased towardsalready established institutions. TDR’s highly customized,integrated, and seamless approach to capacity building andresearch funding represents one of the few mechanisms forresearchers from least developed countries to be involved in,and for building a sustained basis for, research of local andinternational relevance. Partnerships at both the individual and institutional level,networking and promoting equal opportunities, gender andgeographical balance among DEC researchers, constitute thecore of TDR’s approach to building research capacity. Thisapproach has proven highly effective in many countrieswhere TDR continues to collaborate with scientists whoseresearch groups received early support from TDR. Many ofthese groups now participate in the global research agenda,from basic biological and social science to research into hownew policies and strategies are best introduced into coun-tries’ health systems. Many developing countries’ researchand training centres are now also engaged in helping tobuild research capacity in other developing countries.

‘Tacit’ knowledge andskills are different from‘codified’ knowledge asfound e.g. in publishedliterature. Tacit knowl-edge and skills areembodied in people and are learnt throughactual training, e.g. inlaboratories and universities. Diseaseendemic countries(DECs), in particularthe least developed, are losing their tacitknowledge as highly-skilled researchers are finding employmentelsewhere, often result-ing in shifting researchaway from advance-ment of knowledge tocreation of wealth.

Building research capacity in least developed countriesBuilding research capacity in least developed countries


TDR’s research capabilitystrengthening activities have re-flected the changing capacitiesand infrastructures in DECs. InTDR’s formative years, supportconcentrated on large-scale insti-tution strengthening, often involv-ing the provision of crucial equip-ment and support for multi-dis-ease or cross-disciplinary re-search projects.With the evolvingscientific capacities and infrastruc-tures in many DECs in the late1980s, the emphasis shifted to abalance of institution and individ-ual support where priority wasgiven to human resource devel-opment. Research training grantsare awarded on a highly compet-itive basis to applicants with fixedemployment in a relevant re-search or control position, there-

by facilitating a direct impact onresearch and control.With its new strategy,TDR has es-tablished two main tracks in itsapproach to capacity building.One track is driven by the R&Doutput, i.e. leading research insti-tutions, from least as well as moreadvanced developing countries,are invited to compete for par-ticipation in R&D work con-tributing directly to TDR’s R&Dagenda and to build capacities tobecome more internationallycompetitive.The other track is re-served strictly for researchersfrom least developed countriesand aims more broadly to lay sol-id foundations for building futuresustainable research capacities inthese countries.

What was the impact?


TDR has supported over 1000trainees from 416 researchgroups and institutions drawnfrom 76 developing countries.TDR is often considered uniqueamong funding agencies in thatover 95% of its trainees return totheir countries to continue work-ing in their areas of specialty.TDRencourages applications fromwomen, and over one third offunded individuals have beenwomen.The majority of TDR PhDgraduates (60%) have publishedmore in the post-grant periodthan the pre-grant period. TDRgraduates have higher successrates than non-TDR graduates inapplying for re-entry grants (57%versus 30%), and TDR graduates

have similarly higher success ratesin receiving TDR R&D fundingthan non-TDR graduates (theTDR steering committee fundingaverages being 58% and 30% respectively).TDR has played a significant rolein boosting overall research capa-bilities in developing nations. Be-tween 1970 and 1985, the num-ber of skilled people engaged inresearch in Africa rose by a factorof 10 and funds for R&D in-creased 7-fold over the same pe-riod. In the past decade, there hasbeen an extraordinary growth ofscientific knowledge and tech-niques with application to tropicaldisease research. Much of thisknowledge has come from re-

search in developing countries.More importantly, there is a grow-ing ability of these countries tomake use of this knowledge. FromTDR’s viewpoint, the result hasbeen a new cadre of public healthand scientific research leaders andspecialists. Past TDR grantees nowprovide opportunities to trainyoung scientists to develop re-search teams, and to promotepartnerships. Former TDR traineesand supported institutions nowplay pivotal roles in research aswell as in control and health pol-icy making, nationally, regionally,and internationally.

been a major component of TDR since its inception.Over the years, TDR has estab-lished managerial systems and ca-pacity strengthening approacheswhich can handle large numbersof trainees and ensure appropri-ate re-entries and maintenance ofa research base in home coun-tries. The dual role of TDR, as afunding agency for capacity build-ing as well as for actual conductof research and product develop-ment, forms the basis for its com-parative advantage as one of theworld’s lead organizations in re-search capacity building.


TDR’s technologytransfer initiatives aim to help advanceddeveloping countriesimprove their ownresearch and development (R&D)capacities.

Technology transferTechnology transfer

A profound need for new prod-ucts for tropical diseases has longbeen recognized.TDR became in-volved because the pace of emer-gence of drug resistance and con-sequent drug obsolescence, andthe rate at which therapeuticagents were losing their effective-ness, was not being countered bycurrent research.This is partly dueto the lack of activity by agencies,institutions and commercial en-terprises in both the public andprivate sectors in the West,founded on the poor economic

conditions in tropical regions andthe prospective poor return oninvestments.There was – and re-mains – a need for transfer oftechnology to advance and pro-mote research and developmentcapabilities for tropical diseasesthrough collaborative activities.Furthermore, the cost of effectivemedicines is often out of reach forhealthcare programmes in manytropical regions, creating the needfor both discovery and develop-ment of new products for tropi-cal diseases and mechanisms tohelp those most in need get ac-cess to whatever tools becomeavailable. Technology transfer todisease endemic countries might,for example, result in productionof cheaper, and hence more ac-cessible, medicines.Thailand is highly suited as a loca-tion because it boasts a corps ofwell-trained scientists, resources

to support research, more thansufficient patients infected by oropen to infection with target dis-eases, and a broad range of natu-ral products which are sources ofpotential new drugs and activecompounds.

IntroductionAn excellent example of the initiatives in which technologyhas been transferred through TDR activities is the ThailandTropical Diseases Research Programme (T-2). This pro-gramme, established in 1997, comprises an organizationwhich promotes research into new product (drugs, vaccines,diagnostics) development and screening. TDR partners inthis venture are the Thailand Research Fund, and theNational Science and Technology DevelopmentAgency/National Center for Genetic Engineering andBiotechnology of Thailand (NSTDA/BIOTEC).



As a co-founder of T-2, and withits expertise, experience and rep-utation, TDR plays an importantrole in overall programme man-agement. TDR orchestrates re-search assistance to T-2 throughits connections with universitiesand pharmaceutical companies,providing the important interna-tional context to facilitate linkagesand promote 2-way informationflow between Thai and foreignexpertise, and plays a role in theevaluation of research perform-

ance and results and making rec-ommendations for further action.Within the T-2 consortiumarrangements, TDR is the instru-mental factor in building and con-solidating networks of re-searchers and entrepreneurs.From this base,TDR has catalysedresearch on its target diseases (T-2, amongst its other diseases, car-ries out research on malaria,dengue, filariasis and tuberculo-sis). Of special relevance,TDR hassponsored and conducted work-shops on good clinical practice(GCP) and good laboratory prac-tice (GLP).The implementation ofthese practices will ensure thatthe data produced from drug andvaccine development studies are

of high quality and reliable, andtherefore internationally valid.While TDR’s role is in providingthe important international con-text to facilitate linkages, the roleof the Thai partners is in provid-ing the important Thailand-basedresearch context under which T-2 operates, as well as in coor-dination to convene, arrange andcover the costs of all meetings ofthe international advisory andsteering boards.

Within the first two years (1998-99):• technology transfer had oc-

curred through exchange ofThai and foreign investigatorsand training of investigators in specialized fields (e.g. me-dicinal chemistry, screening ofbiological activity) in Thailandand abroad.

• and following the firstTDR/GLP workshop in Thai-land, subsequent workshopshad been conducted in-coun-try by the original trainees.

• a new antimalarial was underdevelopment – a combinationof an artemisinin derivativeplus mefloquine.

• in a high-throughput screeningsystem, 6424 samples of Thainatural products and syntheticcompounds had been

screened using a newly-devel-oped and simplified method,with 985 returning positive an-timalarial indicators. Some arebeing further evaluated.

• researcher had developed a PCR method to detectWuchereria bancrofti in mos-quitos – which could be used as a tool to monitor and eval-uate the filariasis control pro-gramme in Thailand.

• two special tuberculosis labo-ratories had been established.In one, more than 2200 sam-ples of pure compounds andnatural products had beenscreened for anti-TB activity. Inthe other, research is ongoingon characterization of strains of Mycobacterium tuberculosisin Thailand (1567 strains col-lected in first 2 years).




China is now well onthe way to producinga sizeable body ofhigh-class research on schistosomiasis.Research institutionshave been strength-ened, experiencedscientists established,and a much improvednetwork for schistoso-miasis control inChina developed.


Especially important was TDR’srole in advising on, assessing andproviding systems for managingresearch proposals and projects.By sponsoring expert advisors tothe JRMC, 245 projects were selected for support out of morethan 800 submitted for consider-ation, 6 workshops were organ-ized, and 23 young scientists weretrained abroad. In using its oper-ational capability of acting as acatalyst, TDR provided sustainedinput to the mobilizing and galva-nizing of scientists working in academic institutions and staff di-rectly occupied in control activi-ties.

TDR became involved because ofits interest in promoting research,research capacity building andlinking closely with control activi-ties. JRMC was seeking solutionsthrough research and the speed-ing up of implementation of newfindings in the field, a focus ofTDR. It functioned as the re-search arm of the consolidatedeffort to eliminate schistosomia-sis as a public health problem inChina, organizing nationwide co-operative research on commonproblems for policy, managementand methods in schistosomiasiscontrol. Thus the JRMC goals

were in keeping with the TDRgoals of reducing morbiditycaused by neglected tropical dis-eases, and increasing the self-reliance of endemic countries inresearch. The end products ofJRMC, like those of TDR, are so-lutions to public health problems.


IntroductionResearch was a fundamental part of the overall effort forcontrol of schistosomiasis in China, supported by a Worldbank loan. A Joint Research Management Committee (JRMC)was set up to administer the research programme, to whichTDR contributed by supporting the participation of four advi-sors – two staff members and two outside experts. The JRMCstrategy was to ensure cost-effectiveness of the chemother-apy programme, improve health education, encourage devel-opment and implementation of serologic diagnostic tech-niques, develop new approaches to schistosomiasis control,and help raise the quality of management. In 1995, activi-ties became concentrated on surveillance and treatment,with a strong focus on diagnostic techniques, geographicalinformation systems (GIS), prevention of schistosomiasis byapplication of new drugs (artemether), and cost-effectivecontrol management in different types of endemic areas.

Schistosomiasis control capacity in ChinaSchistosomiasis controlcapacity in China


In all, during the seven years, 278theses were published, 25 proj-ects were awarded prizes, and 7 projects generated patents.The development of novel ap-proaches to chemotherapyturned out to be the field wherethe most important discoverieswere made. Several new controltools were produced which mayimprove future control approach-es. Some notable achievementswere:• use of artemisinin derivatives in

prevention of schistosomiasis –a novel application of arte-misinin derivatives (otherwiseused for malaria) which isprobably the most importantdiscovery in the field of schis-tosomiasis in recent years.

• cost-benefit analyses of variousstrategies, e.g. of targetedchemotherapy compared tomass chemotherapy in heavilyendemic areas – targetedchemotherapy was found to becost-effective in highly endem-ic areas.

• advances in immunodiagnosis,including the establishment ofa national reference centrewith provincial serum bank.

• implementation of a new tech-nique to control snails spread-ing with the river irrigation systems (a patent granted onthis technique).

• improved methods for the sur-veillance of cercariae-infectedwater – a new and bettermethod was developed whichis now taught in training cours-es and used in endemic areasof several provinces.

• application and evaluation ofschool-based health educationemphasizing the risk for schis-tosomiasis.

• techniques for rapid evaluationof schistosomiasis in lake andmarshland regions, and the na-tional schistosomiasis surveysfor evaluation of the controlproject after the first five years.

• development, application andevaluation of a rapid diagnostickit for the detection of Schisto-somiasis japonicum circulatingantigen.

• the development of a new mol-luscicide (awarded a patent).

The overall impact on endemici-ty and, particularly, on the intensi-ty of disease due to schistosomi-asis during the seven years wasfavourable. In one province, schis-tosomiasis was declared eradicat-ed and, in others, the number ofvillages classified as endemic wasreduced by 20-50%.As schistosomiasis is now ap-proaching elimination as a publichealth problem in may areas inChina, the researchers who weretrained and given opportunitiesunder this programme are nowmoving on to apply their skills and knowledge to solve otherpublic health problems.



Access to, andexchange of, informa-tion has increasinglybecome a determinantfor progress in science.


Using its full range of in-house sci-entific, communications, and in-formation technology expertise,and working closely with special-ists in its co-sponsoring agencies,i.e. UNDP,World Bank and WHO,TDR has remained at the fore-front of electronic publishing withregard to development and pro-

duction of material on all aspectsof its target diseases and relatedresearch activities. TDR takescomplex, highly specific and oftenjargon-filled scientific research da-ta, and reworks and repackages itin a format easily digestible andunderstandable for disseminationvia the Internet. In addition, TDR

As a network and knowledgemanagement organization, com-munication is an essential com-ponent of TDR's work. Dissemi-nating and providing access to sci-entific and technical informationon target diseases, new controltools and methods, best practices,and research needs and results, isan important part of TDR's ob-jectives. Provision of informationon TDR's progress, transparencyin operations, and advocacy toraise awareness and draw atten-tion to, and support for, TDR'swork, are also of critical impor-tance.Although the so-called 'digital di-vide' still puts researchers fromdeveloping countries at a disad-vantage as compared to their col-leagues from industrialized na-tions, TDR's production of web-

site (and other) CD-ROMs, to-gether with support of initiativesto improve Internet connectivity,aim to narrow the informationgap for TDR scientists.With respect to access to, and ex-change of, information relevant toresearch in tropical diseases,TDRaims to become a world-leadinghub.


Since the invention of the World Wide Web, a revolution inthe way information and data are communicated and sharedhas taken place. In the early 1990s, TDR was among the firstin the area of health research to exploit the potential of theInternet and World Wide Web. In 1993, TDR established anemail listserv, the tdr-scientists list, and a couple of yearslater, TDR published its first web page. Today, with some 1000pages and 350 links to external websites, the TDR websiteforms the backbone of TDR's electronic communications activ-ities, which also include digital photography, CD-ROMs, videoand television. Continually evolving using the latest and mostappropriate technologies, the website represents a majorvehicle through which TDR reaches its target audiencesthroughout the world, and through which researchers canreach each other.

Introduction

Internet communicationsInternet communications

D I S S E M I N A T I O N O F I N F O R M A T I O N , G U I D E

TDR websitePageviews per month by user category (in 2000)

0

5000

10000

15000

20000

25000

30000

April May June July August Sept. October Nov Dec

Industrialized countries

Unresolved/Unknow*

. net*

Developing countries

Non-profit*

. int*

* country of origin unknow

The TDR website and listservhave become important mediathrough which TDR disseminatesand exchanges information. Serv-ing initially as an outlet for pro-viding information on grants,research priorities and deadlinesfor proposals (including onlineapplication forms), the websiteunderwent a major redesign inJune 1999 to also include:• General information on TDR:

strategy, organization, gover-nance, resources and outcomes

• Interactive versions of TDR'sProgramme Report and re-search highlights

• A complete set of TDR's FinalReport Series presenting lead-ing examples of TDR-support-ed projects

• Multimedia resources, includingvideos, and searchable accessto the TDR image library – a unique catalogue of over 12 000 images

• A complete listing of TDR pub-lications and reports availableto download

• Latest news from TDR• Web-based discussion forums

and trainee profiles to facilitate

contact and information ex-change between researchers(in the pipeline).

Key information is simultaneouslyposted on both the website andlistserv, and coordinated use ofother electronic and traditionalpublishing methods ensures thatTDR meets the needs of thosewith zero, poor or unreliable con-nectivity.In January 2001, the TDR websitereceived approximately 70 000pageviews – almost twice as many as the previous year.Over a 5 month period in 1999,250 feedback emails were re-ceived via the site from 60 differ-ent countries.With only 50 subscribers at theoutset, the tdr-scientists list nowhas close to 2000 participants,35% of whom are developingcountry scientists. At least 8% ofvisits to the TDR website originatefrom developing countries. Manyof those visits from unresolved orunidentified locations (61% of thetotal) may also be from develop-ing countries. New content isposted to the website and the list-serv on an almost daily basis.

What are the results so far?maintains a web-based network-ing area on its website, with linksto over 350 related external web-sites and discussion groups – in-formation reported by sub-scribers to the tdr-scientists emaillist and thus of interest to thewider tropical disease researchcommunity. These pages have re-ceived several awards for a 'cleanbill of health', and are among themost frequently visited pages onthe TDR website.Since 1994,TDR's support of par-asite genome projects havehelped to establish databases andblast servers, which are all nowaccessible via the Internet (seeParasite Genome snippet).

TDR website:www.who.int/tdr

tdr-scientists list: To subscribe, e-mail [email protected] and type the following inthe body of the message: subscribe tdr-scientists

L I N E S , I N S T R U M E N T S A N D A D V I C E

‘Good practices’ in preclinical and clinical trials of newdrugs and vaccineshave been used as a standard by drug regulatory authoritiesin industrializedcountries for over 20 years.


TDR became more involved indrug and vaccine developmentfor tropical diseases as the phar-maceutical industry became lessinterested in this therapeutic areaand the need for disease endem-ic countries to play a greater rolein drug and vaccine developmentbecame evident. When TDR be-gan to promote good practices(1999), the facilities and expertisenecessary for implementation ofthese practices were vir tually

non-existent in disease endemiccountries. So TDR began to sup-port transfer of good practices to disease endemic countriesthrough training workshops andproduction of guidelines.TDR produced ethics guidelinesin an attempt to begin the processof strengthening ethical review inbiomedical research in disease en-demic countries. Although inter-national ethics guidelines andstandards for carrying out bio-

medical research do exist, theyare at a theoretical level, and therewas a need for guidelines thatwere practical (operational). TheTDR guidelines will enable localethics committees to developtheir own specific review proce-dures needed to ensure the pa-tient is not exploited. Implement-ing the standard informed con-sent procedures – whereby eachpatient receives an explanation ofwhat the trial is about and gives

IntroductionUse of standard practices ensures that drug/vaccine devel-opment studies are up to acceptable standards. If diseaseendemic countries are to play a greater role in drug and vac-cine development, there is a need to ensure that good prac-tices are followed in order that data produced are high qual-ity, reproducible and acceptable to drug registration author-ities everywhere. A developing country will then be able tomarket the products it has developed in the rest of theworld.All data obtained from preclinical and clinical trials are ulti-mately used by regulators to authorize marketing of the endproduct. Preclinical development of a compound, duringwhich its safety is evaluated and the data obtained used tomake decisions regarding first use of the product in human,involves examining the compounds in vitro and in animalmodels. If results from preclinical safety studies are satis-factory, the compound enters the clinical stages of develop-ment, in which it is examined in human for safety and effi-cacy.Apart from complying with international standards of prac-tice, all biomedical research has to comply with establishedinternational guidelines concerning ethical and scientificreview of the research, including providing patients with fullinformation so that their consent to participate is informed.

Guidelines to good practicesGuidelines to good practices

D I S S E M I N A T I O N O F I N F O R M A T I O N , G U I D E

TDR’s role was to convene meet-ings of experts, prepare guide-lines, and organize training work-shops in disease endemic coun-tries run by experts, in order tosupport training in good prac-tices, produce guidelines to goodpractices, and help in implemen-tation of these guidelines. Theworkshops have been jointlysponsored by TDR and its indus-trial partners [see list].TDR’s op-erational capability in formingglobal partnerships betweenpublic and private sectors hasbeen important in this work.TDR has also set up monitoringsystems for clinical trials and hasthoroughly trained clinical moni-tors in disease endemic countriesaround the world.

Following initial GLP workshopsin the different regions, the train-ing has become self-replicating.Some of the original participantshave conducted similar work-shops in their home countries tohelp build up the needed capaci-ty for conducting preclinical trialsaccording to good practices.TDR has developed guidelines(standard operating procedures)for clinical investigators, a GLPtraining manual, and is developinga GLP handbook to be used as areference quality document indisease endemic countries. As aspin-off, a document to be usedin areas of research that are notcurrently regulated (e.g. basic re-search, discovery studies, proof-of-principle studies, studies to es-tablish pharmacodynamics effectand mechanisms of action) is alsobeing developed by TDR.Demand for the good practiceand ethics guidelines from theTDR documentation center hasbeen brisk. News of the GLPworkshops, in particular, led to asignificant amount of interest –judged by number of enquiriesfrom interested readers of theTDR newsletter. As well, theethics guidelines have been wide-ly distributed; within six months ofpublication they were available inten languages (English, French,German, Laotian, Filipino, Russian,Spanish,Thai,Turkish,Vietnamese),the translations having been fi-nanced by various intergovern-mental agencies, governmentsand industry.Another result of the interest inethics issues was that, to fosterimproved understanding and im-plementation of ethical review ofbiomedical research, different fo-ra have been set up: the Forumon Ethics Committees in Asia and

Western Pacific (FERCAP) coun-tries, Foro Latino Americano deComités de Ética in investigaciónen Salud (Latin American Forumof Ethics Committees in HealthResearch - FLACEIS), Pan AfricanBioethics Initiative (PABIN).An annual course in researchethics is now being offered byThammasat University,Thailand, aspart of its regular activities. Thiswill enable Masters and PhDtraining in research ethics.



Partners

• Joint United NationsProgramme on HIV/AIDS(UNAIDS)

• The pharmaceutical industry (including AventisPasteur; SmithKlineBeecham Biologicals; ASTA Medica)

• Ministry of Public Health,Thailand

• Organisation for EconomicCooperation andDevelopment (OECD)

• Regulatory authorities(IKS, Intercantonal Office for the Control ofMedicines, Switzerland;FDA, Food & DrugAdministration, USA)

• Scientists from diseaseendemic countries

his/her consent to take part in thetrial - presents one of the biggestdifficulties in conducting clinicaltrials in developing countries. Infact, few patients can fully under-stand all the details about thestudy they are participating in, andcareful review by the ethics com-mittee is one of the most effec-tive measures for this.TDR became involved in thetransfer of good practices be-cause of its comparative advan-tage of being able to draw on theexpertise of the global scientificcommunity in both public and pri-vate sectors. Using this to advan-tage, the TDR guidelines were de-veloped in partnership with theworld’s best experts in drug de-velopment. The good practiceguidelines fulfil the need for qual-ity control in research.

L I N E S , I N S T R U M E N T S A N D A D V I C E

Introduction 1 Gwatkin, D.R. and Guillot M. The burden of diseaseamong the global poor. Washington, The Global Forum forHealth Research and the World Bank, 1999

Transformation of a mosquito

TDR (1991) Report of the meeting ‘Prospects for malariacontrol by genetic manipulation of its vectors’.TDR/BCV/MAL-ENT/91.3

Balter, M. (1999) Gene sequencers target malaria mosqui-to. Science, Jul 23;285(5427):508-9.

Catteruccia, F. et al. (2000) Stable germline transforma-tion of the malaria mosquito Anopheles stephensi. Nature405 (6789): 959-962,

Parasite genome 1 Johnston, D.A. et. al. (1999) Genomics and the biologyof parasites BioEssays 21, 131 – 147. John Wiley & Sons,Inc.

New drugs brought to registration 1 Pécoul, B. et. al. (1999) Access to essential drugs inpoor countries: A lost battle? Journal of the AmericanMedical Association, 281(4): 361-367

Xiao, S. et al. (2000) Preventive effect of artemether inexperimental animals infected with Schistosoma mansoni.Parasitology International, 49: 19-24

Andrade, A.L.S. et. al. (1996) Randomized trial of efficacyof benznidazole in treatment of early Trypanosoma cruziinfection. The Lancet, 348: 1407-1413

Politi, C. et. al. (1995) Cost-effectiveness analysis ofalternative treatments of African gambiense trypanosomi-asis in Uganda. Health Economics, 4: 273-287

Reich. M.R. (2000) The global drug gap. Science, 287: 1979-1981.

Getting drugs into wide control use

Pécoul, B. et. al. (1999) Access to essential drugs in poorcountries: A lost battle? Journal of the American MedicalAssociation, 281(4): 361-367

Reich. M.R. (2000) The global drug gap. Science, 287:1979-1981.

Insecticide-treated nets

Lengeler, C., Cattani, J., de Savigny, D. eds. (1996) Netgain: a new method for preventing malaria deaths.IDRC/TDR. ISBN 0-88936-792-2

Unit-dose antimalarial packs 1 WHO (1993). Implementation of the global malaria con-trol strategy, Geneva, Technical Report Series, No. 839.

2 TDR (1994) Treatment seeking for malaria: A review andsuggestions for future research. Social and EconomicResearch in Tropical Diseases Resource Paper No.2.(TDR/SER/RP/94.1).

Partnerships in science

Malaria research: an audit of international activity. Unitfor Policy Research in Science and Medicine, The WellcomeTrust, London. (1996)

Michaud, C. (1998) TDR’s impact on science: a bibliometricstudy. Third External Review of TDR, Reference document2, (TDR/ER/RD/98.2)

Strengthening health research in the developing world:malaria research capacity in Africa. The Wellcome Trust forthe Multilateral Initiative on Malaria, London, (1999).

Schistosomiasis control capacity in China

Yuan, H.C., et.al. (2000) The 1992-1999 World BankSchistosomiasis Research Initiative in China: Outcome andperspectives. Parasitol. Int. 49(3):195-207

Guidelines to good practices

TDR (2000) Operational guidelines for ethics committeesthat review biomedical research. (TDR/PRD/ETHICS/2000.1)

TDR (2000) Standard operating procedures for clinicalinvestigators. (TDR/TDP/SOP/99.1)

TDR (2000) Good laboratory practice training manual.(TDR/PRD/GLP/00.2)

References

WHO/TDRAvenue Appia 201211 Geneva 27

SwitzerlandTel: (+41) 22-791-3725Fax: (+41) 22-791-4854

E-mail: [email protected]: www.who.int/tdr

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