Snippets of Achievement

Snippets of achievement

... THE PAST ILLUMINATING THE FUTURE ...

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

Snippets of achievement

17 examples from the past illuminating the future TDR/GEN/01.1

This document is not a formal publication of the World Health Organization (WHO), and all rights are reserved by the Organization.The document may, however, be freely reviewed, abstracted, reproduced or translated, 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 Mattock Concept and design:Andy Crump and Lisa Schwarb Foreword

TDR’s new strategy represents an evolution of a very dynamic programme. It builds on 25 years of success in research and training in tropical diseases. The document at hand is an attempt to illustrate the strategy by providing examples from the past. The examples have been selected to highlight TDR’s range of expertise, its global leadership in the field, and its unique capability for building and maintaining partnerships, involving public and private sectors, and developing and developed countries alike. For a full account of achievements the reader is referred to the TDR biennial programme reports. The design and layout of the Snippets of Achievement will hopefully appeal to a wide range of audiences including more outside the circles of the Programme’s usual 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 infectious diseases that affect poor and marginalized populations. The Programme specifically focuses on ten tropical diseases: malaria, tuberculosis, schistosomiasis, lymphatic filariasis, onchocerciasis, leishmaniasis, Chagas disease,African trypanosomiasis, leprosy, and dengue. Some of these diseases are the targets for major global efforts of control. The others are also causing major public health problems and are targets for regional and national control efforts, as they affect different parts of the 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 are increasingly 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 gap between the world's 20% poorest population groups and the 20% richest, in terms of death, is wide. If the world’s poor were to suffer the same death rates (from TDR diseases) as the world’s rich, then the gl;obal number of deaths would be reduced markedly - by 97.5% from tuberculosis, 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 excess death amongst poor populations as do the TDR diseases. In addition to the direct suffering caused by tropical diseases, they also adversely affect the socioeconomic development of poor countries and populations. For example, studies have shown that in Kenya, 11% of primary school days are lost to malaria, with the disease also causing losses of 2-6% of the nation’s GDP. In Nigeria, 1-5% of the country’s GDP is lost due to malaria. In the Philippines, schistosomiasis infection causes annual losses of 41.6 workdays, compared to 3.8 lost days in control groups.

Strategy

TDR uses research to find solutions to public health problems related to neglected infectious diseases that affect the poor and disadvantaged.This requires not only close collaboration with disease control programmes and ministries of health, but also with researchers and product developers from industrialized and developing countries. It further requires strong technical and managerial systems and expertise, in addition to sufficient and reliable flows of appropriate resources.

Value-based organization

TDR 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 to basic health care is a human right.“ The enjoyment of the highest attainable standard of health is 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 to internationally accepted ethical principles. • Knowledge is a crucial element in health improvement, and the attainment of self-reliance in research and development in disease endemic countries is key to sustainability. • Closing of the global gap in research and product development between the rich and poor requires collaboration and partnership between the public and private sectors and involvement of research, planning and implementing agencies at international, national and local levels as well as the targeted populations. • It is essential for the successful functioning of TDR that it retains scientific independence, operational 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 participation in research and product development.

Goals

TDR contributes to the attainment of the following goals: • To alleviate inequity and poverty and foster social and economic development in endemic countries through reduction of mortality, morbidity and disability caused by neglected infectious diseases which affect poor and marginalized populations. • To increase research self-reliance in endemic countries for identifying needs and developing solutions to public health problems caused by neglected infectious diseases.

Objectives

The objectives are considered within TDR’s managerial control.Their attainment is the collective responsibility of the whole Programme across diseases, functions, and categories of staff. The attainment 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 controlling neglected infectious diseases which are applicable, acceptable, and affordable by developing endemic countries, which can be readily integrated into the health services of these countries, and which focus on the health problems of the poor. • To strengthen the capacity of developing endemic countries to undertake the research required for developing and implementing these new and improved disease control approaches.

In-house expertise

TDR 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 programme has developed and continues to strengthen its capacity to manage, in an efficient way, a large number of projects which are implemented in partnerships with outside experts throughout the world. A Special Programme

As a special co-sponsored programme,TDR has the advantage of being housed within the UN system, while at the same time, donors and clients have direct managerial authority through the Joint Coordinating 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 providing service in the form of technical guidance, capacity building, and brokerage to bring partners together 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 the process resulting in the product.That is, the products materialize through the joint efforts of many partners, including academia, industry, public and private institutions, and donors from developing and developed countries. TDR has a unique set of operational capabilities, which allows it to bring together the world’s leading researchers and product developers from the public and private sectors, from developing and developed 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 who do not have access to appropriate and cost-effective means to prevent and treat their neglected infectious diseases.TDR reaches the end-users through its clients in public and private health systems and national and international disease control programmes. TDR’s end-products are solutions to public health problems.These will emerge from knowledge generated by research, and from developing, testing, and validating tools, intervention methods, and implementation strategies.The products will range from environmental, through population and systems 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 problems of the poor.

Expected Results

The snippets of achievement in this document are organized according to the six technical expected 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 and control 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 country 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 Snippets of achievement

Examples from the past illuminating the future NEW BASIC

OnchocercalOnchocercal skinskin diseasedisease

Onchocerciasis, also known as river Introduction blindness, has In 1990, the devastating impact of the skin disease accom- plagued millions, panying infection was recognized and began to be quanti- especially in Africa, fied. Onchocercal dermatitis causes a variety of problems, for centuries. The mainly as a result of the incessant and unbearable itching common name that arises from infection and leads to scratching, which in portrays the common turn leads to bleeding and ulceration of the skin, and often perception of the to secondary infection. Disfiguring skin lesions and alter- disease and its public ations of skin pigmentation also arise, while rashes, joint and bone pain, headache and fatigue are commonplace. The health impact – it disease causes lost work and productivity, and schoolchild- causes severe eye ren’s education suffers due to distraction in class caused by problems including the constant itching. It is estimated that 60% of disability permanent blindness, adjusted life years (DALYs) lost due to onchocerciasis can be and shortens life attributed to skin disease. In 1990, of an estimated 15 mil- expectancy by up lion people with onchocerciasis living in Africa, 8-9 million to 15 years. lived in areas associated with severe skin disease and 6-7 But in 1990, another million in areas associated with blindness. impact of this disease Onchocercal dermatitis is now recognized as a major health became known. problem. As well, it carries with it a severe social stigma, compounding the pain and suffering that those infected with the disease already have to live with.

Why did TDR become involved?

Prior to 1990, the social implica- pact of the skin disease. This had tions and cultural aspects of on- not been done before, and no chocercal skin disease had been other agency was working in this totally neglected, especially where field. In its pioneering work, TDR women were concerned. For ex- brought together social scientists ample, in areas of Africa where and biomedical scientists to begin onchocercal skin disease is com- exploring hitherto neglected as- monly found, the beauty of the pects of this disease. skin is culturally and socially extremely important, so the impact of the disease is exacerbated. In 1989,TDR decided to take a com- pletely new approach and initiate work on the socioeconomic im- KNOWLEDGE

What was TDR’s role?

concerns of individuals regarding head of their household suffered onchodermal dermatitis. Affected from the illness. people worried that the skin dis- TDR galvanized governments, ease had an effect on their ability control programmes, other inter- to interact socially, and others national agencies including the complained of being afraid to dis- TDR co-sponsors, researchers close their disease because they and public health workers. It were embarrassed by having con- achieved this by mobilizing and tracted the disease and feared be- partially funding an international ing ostracized. Villagers were up- network of researchers, institu- set by the intensive itching, and tions and donor agencies, mostly cited fatigue and insomnia as se- engaging cross-disciplinary groups rious concerns, also revealing that that had never previously worked 1 in 3 of them were suffering together. from low self-esteem problems The work pioneered by TDR is associated with the disease and now bearing fruit in many other TDR played a leading and unique the social isolation that resulted. areas and diseases. For example, role, opening the door for scien- A further 33% believed they work is being carried out on the tists, agencies and institutions to would never marry because of social stigma attached to infection examine and expose other as- the social stigma surrounding the with leprosy and lymphatic filaria- pects and impacts of diseases be- disease, while 1-2% of the popu- sis, and on a wide variety of psy- yond the usual biomedical ones. lation had considered suicide as a chosocial, socioeconomic and be- TDR initiated and supported direct result of onchocerciasis. havioural aspects of TDR target studies in communities to uncov- Children were at least twice as diseases. er the underlying feelings and likely to drop out of school if the

What were the results?

The impact of TDR’s work has the scope for eliminating the been immense. Firstly, the work disease became obvious. The validated the extent and severity work on onchocerciasis skin dis- of the skin disease problem, ease contributed to the ground- creating awareness of its scale and work for plans, by the African Pro- encouraging the involvement of gramme for Onchocerciasis players from governmental, Control (APOC), to eliminate on- NGO, industrial, academic and chocerciasis based on distribution other communities. It significantly of ivermectin. Furthermore, in- changed the perception and ac- creased knowledge and aware- tions of donor-driven agencies ness of onchocercal skin disease and disease control activities. has made it easier for health Moreover, the gender aspects workers to engage affected com- and differences in how diseases munities in the single-dose, annu- affect people were brought to the al treatment programmes, and get fore. With the advent of the safe their commitment to carry out and effective drug, ivermectin, and pay for the treatment them- to treat onchocercal infection, selves. NEW BASIC

TransformationTransformation ofof aa mosquitomosquito

TDR’s interest in transformation of Introduction the malaria mosquito To date, the only effective control programmes for malaria began in 1991, have been based on control of its vector, the mosquito, but when the vision of increasing resistance to insecticides, combined with their a mosquito unable cost and detrimental environmental impact, has led to the to transmit malaria search for new ways of controlling the vector. In 1994, TDR began to take shape. set up the Strategic Research Molecular Entomology programme to develop new approaches to mosquito control. Using the powerful techniques of molecular biology, the long-term goal is to replace mosquito vectors in the wild with mosquito populations that are unable to transmit malaria parasites. In 2000, a malaria transmitting species of mosquito was transformed through the insertion of a gene which makes them glow green when excited with ultraviolet light. This

Genetically-manipulated green fluorescence gene is used as a model gene and might, mosquito larvae fluoresce at a later stage, be replaced by genes which inhibit parasite when exposed to UV light. development. The insertion of the green fluorescence gene was a breakthrough, although there is still a long way to go - a projected 10 years. Potentially the most problematic step has yet to be overcome - driving transformed mosquitos, carrying genes that prevent development of the malaria parasite in them, into wild populations of mosquitos, after careful assessment of the risks and consequences of such an action.

Why did TDR become involved?

TDR has a number of compara- bear on the problem of trans- cial staying power to see long- tive advantages, when compared forming the mosquito. Another term projects through to com- with other research funding agen- advantage is that, owing to its in- pletion. And transforming the cies, which mean it is in a position ternational backing and base,TDR mosquito was projected to take to orchestrate this visionary has the organizational and finan- up to 20 years to achieve. work. One advantage is that TDR has an international research net- What was TDR’s role? work and a global vantage point from which to identify unmet research needs and to plan and car- TDR engaged global expertise together by TDR, the Wellcome ry through international research from a variety of disciplines and Trust and the MacArthur Foun- programmes which uniquely fill stimulated debate on the poten- dation to discuss promising re- those needs. TDR was able to tial of transformed mosquitos. In search lines in this new approach bring the world’s best minds to 1991, 36 specialists were brought to mosquito control. KNOWLEDGE

Three main areas of research genes into the mosquito genome, partners of international net- were established. Firstly, to iden- i.e. to transform the mosquito, as works. Over 100 projects in 19 tify parasite-inhibiting genes, and was first achieved in 2000. The countries have been supported. key molecules in mosquitos es- third goal was to develop mech- This collaboration and open in- sential for continued develop- anisms for driving selected genes formation exchange produced ment of the parasite.This will pro- into natural populations of mos- excellent results, confirming the vide potential target genes and quitos, including identifying genes feasibility of this innovative ap- molecules that can be introduced affecting the mosquito’s choice of proach to malaria control. into receptive mosquito strains to host (man or animal). make them refractory to malaria. TDR mobilized a broad range of The second line of research was scientists working in relevant fields to develop genetic and molecular of genetics, biochemistry and mo- tools needed to insert selected lecular biology, inviting them to be

What were the results?

Although it was known that the protease inhibitors, transcription tion dynamics, and mosquito ultimate goals would take at least factors) have been documented host-finding behaviour. Possible 10-20 years to fully realize, the in- from Anopheles gambiae mosqui- driving forces have been de- termediate results, the scientific tos. An international effort in scribed (e.g. ability of transpos- advances, are significant and rele- Anopheles genomics research has able elements to spread through vant and proving of immediate been initiated (in 2000) as a new natural populations). New field practical use in areas such as tax- tool for improved understanding data on the population structure onomy and epidemiology. Some and control of malaria parasite of An. gambiae, from studies look- of the results so far are described development in the mosquito. ing at the amount of genetic vari- below. In developing genetic and molec- ation between populations, indi- In understanding the molecular ular tools for engineering a mos- cate the existence of a historical basis of mosquito resistance to quito that is resistant to malaria, or present-day barrier to gene the malaria parasite, major gene the genetic transformation sys- flow of this species, the major vec- loci have been identified where tem described in 2000 was for tor in Africa. These data are im- genes responsible for disrupting Anopheles stephensi, one of the portant for introducing and parasite development in the major carriers of malaria in urban spreading foreign genes into wild mosquito are located (these areas of the Indian subcontinent. vector populations. Through genes later to be transferred to Use of this system, and its appli- cross-breeding of man-biting susceptible mosquitos).The factor cation to the main vector of hu- species with animal-biting species responsible, in susceptible mos- man malaria in Africa, An. gambi- of mosquito, proteins and genes quitos, for activating the gametes, ae, will speed up understanding of thought to be involved in recog- an early stage of the parasites life the physiology of the mosquito nizing human odours have been cycle, was discovered to be xan- carriers of the disease and their identified, and cloning and initial thurenic acid. A number of possi- interaction with the malaria para- characterization of several classes ble receptors, such as enzymes, site, and could lead, ultimately, to of these olfactory genes in An. on the surfaces of mosquito cells, the replacement of wild mosqui- gambiae have been performed. that the parasite recognizes be- to populations with strains of Of course, numerous and impor- fore it invades the cell, have been mosquito that cannot transmit tant scientific, ethical, safety and distinguished. A new cell type – malaria. regulatory issues will have to be Ross cells – was discovered which In order to develop methods to addressed before such a strategy the parasite ookinete stage spread selected genes in wild could be used to control a vec- prefers to invade after crossing mosquito populations, scientists tor-borne disease. the midgut wall. More than 20 im- are developing a thorough un- mune response genes (proteases, derstanding of mosquito popula- NEW BASIC

ParasiteParasite genomegenome

Despite the advances of modern medicine, Introduction the chronic illness, For most parasitic diseases, current therapy often leaves disfigurement and much to be desired in terms of administration, regimen, tox- death that can result icity, and effectiveness. Potential vaccines are a long way from parasitic from market. Our best prospects for identifying new targets infection still threaten for drugs, vaccines, and diagnostics, and for dissecting the the majority of the biological basis of drug resistance, antigenic diversity, infec- global population tivity and pathology, lie in analysing and understanding the parasite genomes. International genome mapping, sequenc- and retard economic ing and gene discovery initiatives are under way for a vari- development. ety of protozoan and helminth parasites. TDR has played an important role in the generation of knowledge about the genomes of the parasites that cause African trypanosomiasis, Chagas disease, leishmaniasis, schistosomiasis, and lymphatic filariasis, and is now focusing on providing capacity to utilize the parasite genome data and on supporting developments in applied genomics and bioinformatics.

Why did TDR become involved?

Widespread and improper use of tion, diversity, autoimmune stimu- most large-scale biotechnology the few treatments and vector lation and poor antigenicity, such initiatives involving sequencing control measures that were once that no vaccine is yet available for and mapping are conceived and cheap, effective, and easy to ad- any parasitic disease. led by scientists in developed minister, has resulted in the ap- Rationally designed strategies, countries.TDR represents one of pearance and spread of resistant based on an understanding of: the few opportunities for scien- parasites and vectors. Even where how parasites develop, survive, tists from disease endemic coun- drug resistance is not yet a seri- and reproduce in their different tries to participate and collabo- ous problem, available treatments hosts; parasite-host and parasite- rate in long-term, far-reaching may require long-term drug ad- immune system interactions; and projects and to acquire the ex- ministration and/or hospitaliza- factors that determine behaviour, pertise necessary to exploit ad- tion, involve regimens that have pathogenicity, drug resistance and vances in biotechnology. not been standardized, or use antigenic variation, represent the compounds that are sub-curative only practical approach to identi- or invoke severe side-effects. In fying new therapies. Sequencing the long term, vaccines are likely and understanding those parts of to make a major impact but the genome that encode this in- progress is impeded by factors formation are key to develop- such as antigenic switching, muta- ment of the strategies. However, KNOWLEDGE

TDR’s role

“The Schistosoma, Brugia malayi Genome projects break the progress reports - a model that (as model filarial nematode), mould of conventional scientific has become standard procedure Trypanosoma brucei, T. cruzi and practice by being collaborative ef- for consortium approaches in Leishmania initiatives fall within forts performed with a service genome projects. the UNDP/World Bank/WHO Special function in mind and with the As the work progresses and en- Programme for Research and wish to disseminate data as wide- ters into the next phase – the Training in Tropical Diseases. TDR ly as possible. As an international- post-genomic phase - TDR’s role ly recognized lead organization in will increasingly be to strengthen resources are extremely limited tropical disease research, TDR the capability of researchers from and its funding is largely ‘pump- was in a unique situation to facil- disease endemic countries and in- priming’ to facilitate development itate and support the creation of volve them in collaboration with of resources, strategies and international collaborative net- the genome networks in order to collaborations to support applica- works.TDR's unique position pro- exploit the data generated by the tions to national or international vided an umbrella for convening genome projects in developing agencies for larger-scale projects. international experts and giving new tools for managing the dis- This ‘pump-priming’ is beginning scientists from disease endemic eases. TDR efforts will now focus to bear fruit, with the Leishmania countries the opportunity to par- on facilitating the acquisition of and T. brucei genome initiatives ticipate. The Special Programme expertise in bioinformatics and recently attracting multi-million status of TDR also provided the applied genomics by diseases en- 1 dollar support” opportunity for developing part- demic country scientists. TDR's nerships with other agencies and continued support for the institutions to facilitate making the genome networks makes it pos- information available in public sible to organize international databases. TDR's convening posi- training programmes for transfer tion also facilitated a forum for and impact of these technologies presentation and discussion of in disease endemic countries.

Parasite genome initiative web sites: What were the results? Leishmania network: www.ebi.ac.uk/parasites/leish.html Trypanosoma brucei network: Parasite genome discovery has analysis provide ideal opportuni- parsun1.path.com.ac.uk/ been hugely successful and has ties for researchers from disease Trypanosoma cruzi network: www.dbbm.fiocruz.br/ resulted in a logarithmic increase endemic countries to be at the genome/tcruzi.html in the catalogue of known para- cutting edge in this field of re- Schistosoma genome network: site sequences. The parasite search, without being disadvan- www.nhm.ac.uk/hosted_sites/ schisto/ genome projects are generating taged by poor infrastructures.The Filarial network: large amounts of data in diverse coming years are likely to see helios.bto.ed.ac.uk/mbx/fgn/ forms.These data are of wide in- huge improvements in technolo- filgen1.html

terest as they pertain to groups gy that will transform molecular Coordinating sites of organisms that are traditional- biology from an analytical science Parasite genome: ly under-researched. All the para- into a discipline of structure and www.ebi.ac.uk/parasites/ site genome databases are in the functional analysis, and into a parasite-genome.html WHO-TDR parasite genome public domain, available both powerful resource for in vivo ma- committee: www.who.ch/tdr/ through the Internet and for lo- nipulation in order to identify workplan/genome.html cal installation. Therefore, ‘post- new targets for the development Parasite genome mailing list archive: www.mailbase.ac.uk/ genomic’ investigations that ex- of diagnostics tests, drugs and lists-p-t/parasite-genome ploit the databases for functional vaccines. NEW AND

MDTMDT forfor leprosyleprosy

Introduction Leprosy can be traced back at least 2500 years, making it one of the oldest recorded diseases afflicting humans. A chronic disease caused by a bacillus, which can be transmitted via droplets from the nose and mouth of infected people, it affects the skin and can cause nerve damage, eventu- ally leading to hideous deformities. It has struck fear and loathing in the hearts of communities down through the ages, with millions being cast out, banished to leper colonies, often disowned by their own families and loved A researcher in ones. Poverty is a significant factor in preventing control of Bombay who inter- this dreaded disease. Ignorance of the disease has also viewed women on what played a major role. However, administering a cocktail of dif- they considered to be ferent drugs in specific dosages – multidrug therapy, or MDT the most difficult part – can cure leprosy and should lead to its elimination. of coping with leprosy, found that ‘it was touch more than anything, that women longed for, and the loss of this intimate right symbolized such isolation and rejection.’

Why did TDR become involved?

When TDR was founded in 1975, years of continuous treatment, of- Mycobacterium leprae (the mi- it took a leading role in leprosy ten for life, and relapses were a croorganism which causes lep- research, strongly based on the continual threat. Of the other rosy) but was extremely expen- promises offered by molecular bi- drugs used, clofazimine could sive and produced adverse side- ology, especially with a view to cause dark discoloration of the effects. Even as the programme providing new control tools. By skin, thus increasing the severe was being established, TDR’s the early 1970s, drug treatments trauma of those who already had founders recognized the failure of were becoming ineffective. Ther- to live with the unbearable social mono-therapy and set the two- apy with the cheap and readily- stigma and sense of isolation that fold goal of improving drug effec- available drug dapsone was inter- leprosy induces. Another drug, ri- tiveness and reducing the dura- minably long and drug resistance fampicin, already used extensively tion of drug treatments. was becoming increasingly evi- in the treatment of tuberculosis, dent. Leprosy therapy meant had rapid bactericidal effect on IMPROVED TOOLS

What was TDR’s role?

In close collaboration with the through to completion. As an in- sources, following through on WHO leprosy programme, TDR dependent and trusted broker, products that may not prove orchestrated and funded work on TDR could organize and oversee commercially profitable. leprosy drugs, mapping dapsone field trials in disease-endemic The work revealed that combina- resistance (a long and arduous countries. It could also persuade tion therapy was extremely effec- process) to establish the scale of pharmaceutical companies to en- tive and, in 1981, WHO recom- the problem. TDR worked with gage in trials of their drugs along- mended the use of multidrug research groups, scientists, nation- side those from other manufac- therapy (MDT) for the treatment al leprosy programmes and turers, stimulate and engage sci- of leprosy, based primarily on NGOs, coordinating large-scale entists, researchers and govern- TDR’s findings.TDR continued the drug combination trials in India ments. And it could provide fi- research to both improve the and Africa and seeing them nance and mobilize further re- drug combinations being used and reduce treatment durations, working closely with the WHO Global impact of MDT on Leprosy leprosy programme. This contin- (in millions from 1985 to 2000) ued commitment resulted in var- 12 ious other drugs being investigat- ed, and the so-called ‘ROM’ com- 10 binations (comprising rifampicin, 8 ofloxacin and minocycline) were developed and introduced as ‘re- 6 fined products’ in 1997, some 16 years after MDT had become 4 WHO recommended therapy. 2 Other new drug regimens are still under trial.The hope is to reduce MDT treatment duration to 1985 86 87 88 89 90 91 92 93 94 95 96 97 98 99 2000 weeks, or possibly even to days.

Prevalence Cured with MDT

What were the results?

The work of TDR and its partners 2001. Early detection and treat- a major contribution in providing has brought huge returns. Drug ment with MDT has prevented MDT free of charge to all leprosy combinations produced a highly some 3-4 million people from be- patients.Along with TDR,they are effective treatment strategy, and ing disabled. However, there is a crucial players in ensuring that re- the leprosy bacillus has not de- need to detect and treat about search on the transmission and in- veloped any resistance to MDT. 2.5 million new cases over the cidence of leprosy, on improved Since the introduction of MDT, next five years to achieve elimi- methods of detection and on pre- there has been a dramatic reduc- nation. The Japanese-based Nip- vention and management of tion in prevalence of leprosy, from pon Foundation has played a lead- nerve damage, continues and that 5.4 million registered patients in ing role in bringing the elimination MDT is widely employed to attain 1985 to around 0.75 million at the of leprosy closer to fruition, to- the goal of eliminating leprosy and beginning of 2000.The disease has gether with the Novartis phar- ridding the world of one of its been eliminated from 98 coun- maceutical company and Novar- most dreaded diseases. tries and the global leprosy elim- tis Foundation for Sustainable De- ination targets will be met in velopment, which has also made NEW AND

NewNew drugsdrugs broughtbrought toto registrationregistration

According to an Introduction analysis by Pécoul et. al.1 of the 1233 new The problem is market failure. Drug research and develop- drugs identified as ment is so costly in terms of time and money, that, in the reaching the market face of counterfeit drugs and circumvention of patent rights between 1975-97, only in some countries, together with non-solvent populations, 13 were approved there are no market incentives to motivate the pharmaceutical industry. Unless commercial returns will be good and/or specifically for tropical risks reduced, the industry (with few exceptions) will not diseases. Of these 13, invest time and resources in drugs for tropical diseases. six were developed with Six of the 13 drugs identified by Pécoul et. al. – artemether, TDR support. mefloquine, eflornithine, albendazole, ivermectin, and lipid associated amphotericin – were developed with TDR help. Other drugs which have received TDR input and are now registered for use include: mefloquine + pyrimethamine combination, and artemotil for malaria. Also, TDR supported trials of benznidazole for early chronic Chagas disease, praziquan- tel combinations for schistosomiasis, and albendazole combinations for lymphatic filariasis. In total, TDR has helped bring 13 new chemical entities to registration or recommendation for use in the control of tropical diseases, and others are in the pipeline.

Why did TDR become involved?

TDR’s end-products are solutions exploit the comparative advan- facilitates transfer of knowledge to public health problems caused tages of each partner.By doing so, and technology, and provides di- by neglected infectious diseases both the costs and the risks in- rect technical support to all affecting poor and marginalized volved can be significantly re- stages of the processes involved populations. Drugs constitute duced and the relevance of the in bringing new drugs to registra- many of these solutions – drugs outcome ensured. TDR not only tion or recommendation for use are the mainstay of most public provides direct funding, but also for disease control programmes. health programmes aimed at reducing mortality and morbidity in the developing world. The centrepiece of TDR’s opera- What was TDR’s role? tional capability is its ability to bring together the public and pri- TDR’s role can begin anywhere its clinical development and reg- vate sectors, industry and acade- between the discovery of a new istration.TDR brings partners to- mia, developed and developing therapeutic target for compound gether, providing strategic funding countries, in partnerships that identification and the last stages of and technical support, and organ- IMPROVED TOOLS

izing small and large-scale field tri- Ivermectin, was originally dis- in the clinic). A TDR-supported als in endemic countries following covered and developed by Merck study of metabolic pathways in standards and regulatory require- & Co. Inc. for use in animals, but trypanosomes led to the demon- ments compatible with registra- later, TDR provided substantial stration, in mice, that eflornithine tion in developed countries. Some financial resources and technical was effective against the enzyme examples are: input for multi-country trials ornithine decarboxylase, a key en- Artemether, a derivative of against onchocerciasis. Ivermectin zyme in the multiplication of try- artemisinin, discovered and devel- is the major tool for treatment panosomes. TDR supported the oped by Chinese scientists, for and control of onchocerciasis. work which led to registration of malaria. In partnership with More recently, TDR-sponsored eflornithine for use in sleeping Rhône-Poulenc Rorer,TDR spon- studies demonstrated that iver- sickness in 1990. But, eflornithine sored, coordinated and provided mectin used in combination with is expensive to produce so TDR technical support for clinical trials Albendazole in annual, single funded studies to find a new route of artemether injection, and fur- doses, is effective for the control of synthesis, although these have ther development of regulatory of lymphatic filariasis in Africa. not yet borne fruit. Hoechst data for its use in malaria. TDR also supported studies that Marion Roussel (now Aventis) Also, since the early 1990s, demonstrated albendazole, toge- granted a licence to produce evidence for prophylactic effects her with diethylcarbamazine eflornithine to WHO, which is of artemether on juvenile forms (DEC), to be effective for the con- working with MSF to identify new of various species of schistosome trol of lymphatic filariasis in the manufacturers. has been accumulating. Studies by rest of the world. In the case of Benznidazole for Chagas dis- TDR and its partners have shown albendazole, the industrial partner ease.TDR/backed studies showed that this drug could play a role in is Smith-Kline Beecham (now that treatment of children in the breaking the transmission of schis- GlaxoSmithKline). early chronic phase of Chagas dis- tosomiasis in certain areas (where Eflornithine for African try- ease with benznidazole, to stop it has already been very much re- panosomiasis was discovered the disease evolving to irre- duced, but final eradication has through basic science (it was orig- versible cardiac lesions, is effec- proved difficult, e.g. Saudi Arabia, inally developed by Hoechst Mar- tive. (Benznidazole was previous- Morocco) and in control in cer- ion Roussel for treatment of can- ly only used in the acute phase of tain areas (e.g. Egypt). cer, but proved to be of little use Chagas disease).

What were the results?

Artemether is now registered Eflornithine is licensed for use expand its global network of re- in over 30 endemic countries for in sleeping sickness in the US, Eu- searchers and developers capable intramuscular injection in treat- rope, and 12 African countries. of addressing all the aspects of ment of severe malaria. Treatment of children in the ear- R&D required to bring new drugs Artemether can be recom- ly chronic phase of Chagas dis- from the earliest stages of dis- mended for treatment of schisto- ease with Benznidazole has be- covery through to registration. somiasis in areas where there is come common practice through- TDR is a leading partnership no regular transmission of malar- out Latin America and guidelines builder in this field. ia (e.g. north of the Sahara and for clinical management have Several new organizations are parts of the Middle East). been published. now trying to replicate the mod- Lymphatic filariasis has been tar- Not only has TDR’s work led to els developed by TDR, particular- geted for elimination by 2020. making these drugs available for ly in relation to building partner- The key strategy is mass treat- use in disease control, the work ships between the public and pri- ment with a single, annual dose of has also resulted in TDR,over the vate sectors. two-drug treatment: DEC plus al- years, being able to refine and fur- bendazole, or ivermectin plus ther develop its strong and cus- albendazole. tomized managerial systems and NEW AND

RapidRapid mappingmapping forfor onchocerciasisonchocerciasis

When ivermectin became available Introduction for the treatment of In OCP countries, control was based on tackling of the black- onchocerciasis, and fly vector through aerial spraying of insecticides over its its potential for mass breeding sites in fast-flowing rivers. The advent of iver- treatment became mectin presented a tool which could be used as the main apparent, 85% of the strategy for control in the remaining endemic areas not suit- infected population able for the OCP type of vector control. However, at first lived outside the range there was a huge bottleneck because it was not known on of the Onchocerciasis which areas and communities ivermectin treatment should Control Programme in be focused. It was necessary to first determine the geographical distribution of the disease across countries or West Africa (OCP). regions, and identify the particular communities to treat, before control programmes based on mass treatment could begin. Thus, TDR helped develop a new tool to rapidly assess the onchocerciasis situation – rapid epidemiological mapping of onchocerciasis (REMO). Using REMO, it is possible to assess quickly and cheaply which communities are at high risk and where they are located. Basically, REMO works by using geographical information, particularly the presence of river basins, to identify communities likely to be at high-risk. A sample of these high risk communities is then assessed rapidly for the prevalence of onchocerciasis (by feeling for onchocercal-worm-containig nodules in 50 adults per village).

Why did TDR become involved?

In anticipation of the need for quest from the field. The key ac- to distribute ivermectin, but were rapid tools for identifying com- tors in onchocerciasis control faced with the huge problem of munities endemic for onchocer- outside the OCP area at that time how to identify which communi- ciasis, TDR had developed and were a group of international ties to treat. The coordinating field tested methods for rapid non-governmental development group identified the need for a community diagnosis of on- organizations (NGDOs) working means for rapid mapping and, chocerciasis using palpation for in blindness prevention.They had knowing TDR to be involved in onchocercal nodules in a sample established a coordinating group research on rapid assessment of of 50 adults. But TDR’s involve- with its secretariat in the WHO onchocerciasis, they turned to the ment in research on rapid map- Programme for the Prevention of Programme for help. ping followed from a specific re- Blindness. The NGDOs wanted IMPROVED TOOLS

What was TDR’s role?

In developing REMO,TDR built on oped in several stages – an earli- priority areas for mass treatment. the experiences of the On- er edition was produced after the TDR also carried out the first im- chocerciasis Control Programme initial trial in Cameroon, which plementation of REMO, its first (OCP), whose detailed mapping was later revised after a major large-scale application, under of onchocerciasis had led to un- workshop in Nigeria, where first funding from the World Bank. derstanding of the spatial distri- application of the tool on a na- Several countries were complete- bution of the disease, particularly tional scale was planned. Guide- ly mapped, including Nigeria, its relationship with river basins lines for analysis of REMO results Cameroon, Tanzania and Uganda. and potential blackfly breeding were subsequently developed Further implementation of sites. TDR’s role in developing to help onchocerciasis control REMO was taken over by APOC REMO was catalytic and very personnel interpret results from in 1996, after establishment of this proactive. It brought everyone to- REMO and use them to identify Programme. gether and got the process start- ed. The need for REMO came from the field, but development of the method was driven from in- side TDR.At that time,APOC had not been established, although subsequently TDR was to work closely with this body. TDR also worked closely within WHO with HealthMap, to develop a geographical information system (GIS) for analysis of the onchocerciasis data. After developing REMO,TDR was involved in further standardizing the tool in conjunction with on- No REMO yet chocerciasis control personnel. No CDTI The REMO manual was devel- CDTI unlikely (to refine) Definite CDTI areas CDTI likely (to refine)

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

What were the results?

REMO has become a key tool plete country maps, targeting the plan which communities to treat in the control of onchocerciasis areas for treatment, are available. and obtain better estimates of the and is used to provide basic in- Integration of REMO results in a number to be treated and the formation for rational planning GIS, overlapping the onchocerci- number infected, as well as a bet- of large-scale ivermectin treat- asis map with a population map, ter estimate of the burden of this ment in APOC countries. Com- allows control programmes to disease. NEW AND IMPROVED

VectorVector controlcontrol forfor ChagasChagas diseasedisease

Chagas disease, Introduction caused by the parasite Trypanosoma cruzi, Some 45 000 deaths occur annually from Chagas disease. The exists only on the disease is difficult to diagnose in its early stages, with most American continent, infected people not exhibiting any significant clinical symp- where it is endemic in toms. However, some 45% of infected individuals move on to 18 countries of Central the chronic stage, with irreversible damage to the cardiac, digestive or neurological tissues, for which no treatment is and South America. available. In the whole of Latin The disease usually afflicts people in rural areas and those America in 1991, living in poor communities where houses are built from very an estimated basic materials. Roofs are generally made of dried straw with 16-18 million people mud-plastered walls, providing a haven for the bloodsucking were infected and triatomine bugs which transmit the disease to humans. In another 100 million recent years, the disease has also become a concern in urban people were at risk areas as well, when people migrate into the cities with the of becoming infected. parasite already in their bloodstream. Here, the disease is transmitted via blood transfusions. Canisters, which release pyrethroid insecticidal fumes when lit, have been developed and deployed in the fight against Chagas disease since the 1980s. They are designed for use by householders themselves. TDR also supported the development of insecticidal paints, for use by spray teams. These paints retain their insecticidal activity longer than traditional sprays.

Why did TDR become involved?

In 1977,TDR’s Scientific Working tribution, prevalence and clinical Group on Chagas Disease identi- varieties of Chagas disease and of fied several urgent needs: devel- the distribution of its vectors. opment of new drugs; improved By the early 1980s, it was recog- methods to eliminate the parasite nized that the only feasible means from blood banks; better diag- of controlling Chagas disease was nostic testing; improved vector through attacking the insect vec- control methods. There was em- tor with insecticides. Housing im- phasis on gaining better under- provements were seen as a com- standing of the geographical dis- plementary viable option. INTERVENTION METHODS

What was TDR’s role?

Along with regional organizations development of the canisters and bilateral agencies,TDR played from 1980, organized and part- a crucial role in helping mobilize funded multicountry studies of resources at the global level to fi- the new vector control tools (in- nance research on Chagas dis- secticidal paints and fumigant can- ease, and in international coordi- isters), and helped establish a nation and linking of researchers, standard protocol to evaluate the particularly those in endemic studies. In most countries, the countries, but also those in North paints were shown to reduce America and Europe. The result rates of house infestation by a fac- was the establishment of a net- tor of 2-3 compared with con- work of national institutions, ventional spraying and to provide working in collaboration with an improved living environment. government control programmes. The canisters, which are now pro- Scientists at the Centro de Inves- duced and marketed by local in- tigaciones de Plagas e Insecticidas dustries, are employed optimally (CIPEIN) began collaboration to maintain insecticide levels in- with TDR in 1978. TDR funded side houses.

What were the results?

Argentina, Bolivia, Brazil, Chile, Paraguay and Uruguay began the ‘Initiative for the Elimination of Chagas Disease by Southern Cone Countries’ in 1991, using fumigant canisters as one of the tools to achieve this goal. In the Southern Cone nations, house infestation with triatomine vectors fell by up to 90% between 1982 and 1994. Disease transmission by vectors and blood transfusion has now been halted in Uruguay, Chile and PARTNERS Brazil. Interruption of transmis- (fumigant canisters) sion in Argentina, Bolivia and Paraguay is expected by 2003. • Ministry of Health (Argentina) The fumigant canister is now al- • National Research Council so being evaluated to fight an- (Argentina) other disease vector, the mosqui- • CHEMOTECHNICA, SA to Aedes aegypti, which transmits (Argentina) the virus causing Dengue. NEW AND IMPROVED

Insecticide-treatedInsecticide treated nets

Trials have shown that the use of Introduction insecticide- treated Treating nets with a biodegradable pyrethroid insecticide has nets protect sleeping added to their efficacy. The first TDR studies in 1990-91, in children from being the Gambia, showed a reduction of 63% in mortality from all bitten by mosquito causes in children between the ages of one and five who had vectors, resulting in slept under treated nets. Later trials in other countries dramatic reductions showed lesser, but still significant, reductions in mortality – of 33% in the Kenyan trials and 17% in the Ghanaian trials. in deaths among In the Kenyan trials, the nets not only prevented deaths but children under five. also led to a 40% reduction in hospital admissions for severe malaria, indicating that their use could reduce the burden on health services. The results of the trials suggested that some 500 000 African children might be saved each year from malaria-related mortality if the nets were widely and proper- ly used. As well as demonstrating the efficacy of treated nets, TDR supported work to improve methods for their treatment with insecticide.

What was TDR’s role?

TDR’s played various role, acting communities and illiteracy was as a forum for ensuring that treat- not found to be a problem, al- Why did TDR ed nets get taken more seriously though at the outset, the idea of get involved? in the prevention of malaria, pro- a dip-it-yourself kit for use in de- viding evidence of their efficacy. veloping countries had been re- TDR also helped to work out garded with scepticism by most TDR became involved because of strategies, along with WHO, for people, including public health au- its comparative advantage in see- product development and ways thorities and chemical manufac- ing large-scale field trials through of sustaining access to nets in turers.TDR also answered misgiv- to completion. This is due to its communities. ings about the use of nets. One organizational and financial staying Another role was to stimulate the concern was that use of the nets power made possible by its inter- private sector – the pesticide pro- would induce pyrethroid resist- national backing and base. The ducers – to develop formulations ance in the mosquito population. TDR trials were the largest trials and packaging adapted for home But TDR studies indicated that, with nets ever carried out, involv- treatment of nets. Dip-it-yourself even in areas where there is such ing altogether almost half a million kits were designed, along with a resistance, treated nets remain ef- people, 20 research institutes and instructions for safe and effective fective, and their use is unlikely to donors.They were carried out in use of the kits, including where lit- induce resistance in malaria vec- different epidemiological settings eracy is low.The instructions were tors. Another concern was that with different malaria risks. well tested in urban and rural use of treated nets in hyper- INTERVENTION METHODS

endemic malaria areas might from TDR-supported studies in- merely shift the predominant age dicate that delaying infection is of mortality to a higher age group not a problem. – that as children may not be in- Insecticide treated nets provide fected early in life, they will not one of the best malaria control develop partial immunity to measures to date, and TDR oc- malaria, and so will succumb to cupied a catalytic role to bring it the disease later in life. Findings all together.

What were the results?

The findings of the efficacy trials vector mosquitos, and is one of African countries, under the RBM emphasized that the contribution the main strategies adopted by banner, of 60% coverage of of malaria to child mortality in Roll Back Malaria.WHO’s Region- people at risk from malaria with Africa had been underestimated al Office for Africa asked for a nets by 2005, there will be much and that potentially large benefits ‘phased and continuously moni- collaborative implementation re- are to be gained from malaria pre- tored implementation of treated search, including integration of in- ventive interventions. nets’. Overall, it is estimated that, secticide-treated net activities The demonstration of efficacy of at the present time, less than 5% with other health interventions the nets encouraged the private of people at risk of malaria in e.g. integrated management of the sector to undertake product de- Africa, south of the Sahara, use sick child and mother-and-child velopment and bring new innova- nets. However, the figures range health. tions to the market (‘dip-it-your- widely between different coun- self’ kits; more durable nets; bed- tries: nets that don’t need re-dipping). • In Nigeria, evidence shows that The first trials of treated bednets, less than 2% of the population PARTNERS in the Gambia in 1990-91, are aware of the effectiveness Funding partners: demonstrated their efficacy to of treated nets while less than • United Nations Children’s public health officials in the coun- 1% actually use them. Fund (UNICEF) try, who became aware that treat- • In Tanzania, more than 70% of • United States Agency for ed nets are a very cost-effective households in Dar es Salaam International Development tool for fighting malaria, ranking and more than 20% of house- (USAID) with some of the most efficient holds in many rural areas have • International Development Research Centre (IDRC) health interventions available (e.g. at least one net. • Centers for Disease childhood immunizations). After • In The Gambia (the only coun- Control (CDC) this, the Gambian government ini- try where nets are used on a • Canadian International tiated a country-wide programme wide scale), over 76% of the ru- Development Agency for the implementation of net im- ral population have, and do use, (CIDA) pregnation in villages with primary nets. • Wellcome Trust health care clinics. • In Vietnam, the number of peo- • Save the Children Fund • London School of Hygiene People’s attitudes to nets are ple protected by treated nets and Tropical Medicine changing, with more and more increased from 300,000 in 1991 • Italian Cooperation households taking to them as to almost 10.8 million in 1998, people recognize that using nets although it is estimated that half Funded partners: Ministry of Health of: is a way to save the lives of their of the population of 75 million • Ghana children. is at risk of malaria. • Tanzania Today, the use of treated nets is Thus, TDR has helped prove the • The Gambia an important part of the global principle of efficacy of treated • Kenya strategy proposed by WHO to nets. But the challenge ahead is • Burkina Faso prevent people being infected by not insignificant. With the goal for NEW AND IMPROVED

Unit-doseUnit-dose antimalarialantimalarial packspacks

Early diagnosis and prompt, effective treat- Introduction ment of malaria is a The majority of families treat their children at home using key strategy for malar- antimalarials and/or antipyretics bought from drug vendors ia control.1 The role and/or village shops as the first line of treatment. However, that home treatment families often buy insufficient amounts, there is very little can play in this strate- information provided with the treatment, and even when gy, especially for they do receive the full course, compliance with treatment Africa, became appar- recommendations is poor. The tendency is to stop treatment as soon as the symptoms disappear, saving any remaining ent after better under- tablets for future illness episodes. Despite these shortcom- standing of care seek- ings, at the Abuja Summit in April 2000, the heads of state ing behaviour was of most African countries, in the context of Roll Back Malaria reached. (RBM), committed themselves to ensuring that diagnosis and treatment of malaria is made available as peripherally as possible, including home treatment, in an effort to make appropriate treatment available and accessible to the poorest groups in the community.

Why did TDR get involved?

TDR funded many of the studies community awareness for early stone of the home management in treatment seeking behaviour 2 appropriate home treatment, package of interventions that have that prompted the new strategy prompt referral of severely ill chil- been developed further and test- for malaria control adopted by dren. These early, very localized ed through multi-country studies. the Roll Back Malaria initiative. experiences formed the corner- Through the work of the various task forces in its Applied Field Re- search area, TDR had established a network of interested and able What was TDR’s role? teams in countries who could carry out the research.The initial ex- ploratory studies, formulated TDR’s role has been to identify tiveness and impact of home mainly in the context of health possible problems that might im- treatment on the malaria burden. sector reforms, had identified po- pact on the effectiveness of home In 1998, TDR constituted a task tential interventions e.g. training treatment, to urgently develop force of experts who took re- of shopkeepers and vendors, unit- and implement strategies to solve sponsibility for these activities and dose packaging of antimalarials to these problems, and to provide committed themselves to work- improve compliance, improving conclusive evidence of the effec- ing with multi-country, multi-disci- INTERVENTION METHODS

plinary teams to provide, within five years, the answers to the following questions: Is it possible and feasible to change the behaviour and practices of mothers, households and communities in order to increase the extent of early,appropriate care for childhood un- complicated fever episodes and referral for severe illness in malaria endemic countries? If strategies which prove feasible and effective Country teams (Ghana, Nigeria, in changing behaviour and prac- Uganda, Burkina Faso) were se- tice were to be implemented on lected on a competitive basis. A a much wider scale, would they common framework was devel- have an impact on morbidity and oped and proposals were devel- mortality? oped along this framework. Fund- ing and technical support was provided to the teams.

What were the results?

To date, results have been ob- agement team, which was calcu- and between 8.1% and 18.2% in tained from the Burkina Faso tri- lated to allow for full recovery of the control group. al. In Burkina Faso, researchers de- the purchase costs and a 10% in- The feasibility, sustainability, cost signed a strategy for prompt and centive margin for the volunteer. and effectiveness over time of the adequate home treatment that in- Three hundred and seventy-five strategy for home treatment of cluded: re-training of health staff villages participated in the study malaria have not yet been of the local health unit, informa- and at least one volunteer was demonstrated on a larger scale. tion/sensitization meetings and trained in each village. Fifty-six per This is a challenge for implemen- training sessions for communities cent of the children that were tation research. from all study villages, and making treated by the village volunteers available pre-packaged antimalari- complied with the treatment, in- al drugs containing a full course of cluding the correct duration. treatment through trained village The rate of progression towards volunteers. The drugs were pro- complicated malaria was lower in vided in four different colour children who were treated with coded simple packages for differ- pre-packaged antimalarials (5.1%) ent age groups, following the than in those not treated with PARTNERS Burkina Faso treatment guidelines these drugs (11.0%). The overall (0-6 months, 7-11 months, 12-35 reduction of progression towards • National institutions months and 36-69 months), each severe disease among users of and ministries of health containing a full course of treat- pre-packaged treatment was • USAID (US Agency ment and a label with pictoral in- 53.6%. In the four target age for International structions on how to administer groups, the progression rate to Development) the drugs. A village volunteer sold severe malaria varied between • Roll Back Malaria the drugs at a price previously 3% and 7.1% in children who re- • Wellcome Trust agreed with the local health man- ceived pre-packaged antimalarials, NEW AND IMPROVED POLICIES, PREVENTION

Community-DirectedCommunity-Directed TreatmentTreatment

Community Directed Introduction Treatment (ComDT) is a new approach In ComDT, the community is empowered to take full respon- to drug delivery in sibility for the drug delivery process, to collectively decide how and when to do the treatment, and to ensure adequate which the community implementation and follow-up. A TDR multi-country study is in charge of demonstrated, in 1995, the effectiveness of ComDT for iver- the planning and mectin delivery. The method has subsequently been adopted execution of treatment by all onchocerciasis endemic countries in Africa as the prin- of its own members. cipal strategy for drug delivery in onchocerciasis control. Since then, ComDT has proven very effective in achieving the treatment coverage required to eliminate onchocerciasis as a public health problem, and in 2000, some 20 million people received ivermectin treatment through ComDT. A recent external evaluation of the African Programme for Onchocerciasis Control (APOC), which covers 16 endemic countries in Africa, concluded that ‘ComDT has been a time- ly and innovative strategy ... and communities have been deeply involved in their own health care on a massive scale ... ComDT is a strategy which could be used as a model in developing other community-based programmes’.

Why did TDR get involved?

Onchocerciasis is a major public chocerciasis in 1987, the devel- sure large-scale ivermectin treat- health problem, caused by infec- opment and testing of a control ment, often using mobile teams. tion with Onchocerca volvulus, strategy based on mass iver- To eliminate onchocerciasis as a which results in visual impairment mectin treatment, and the deci- public health problem, annual and blindness, severe skin disease sion by Merck & Co. Inc. to do- treatment needs to be sustained and maddening itching. The dis- nate the drug (Mectizan ®) free over a very long time. Several at- ease has been controlled in the of charge for onchocerciasis con- tempts were made, therefore, to West African savanna by the On- trol for ‘as long as needed’. integrate ivermectin delivery in chocerciasis Control Programme In spite of this breakthrough, primary health care, or to use in West Africa (OCP). But in the large-scale ivermectin treatment community-based approaches in other endemic areas, where more took off only slowly, as it was the many areas where health fa- than 80% of all infected people difficult for the health services cilities were absent or not func- live, OCP’s vector control strate- to provide the required annual tioning. As it was not at all clear gy was not feasible and these round of mass treatment for how effective these different ap- countries were “left looking over onchocerciasis, a disease of the proaches were, TDR was re- the fence”. This changed with the poorest communities 'at the end quested to evaluate them with a emergence of ivermectin as an ef- of the track'.As a result, it was ini- view to developing improved de- fective microfilaricide, its registra- tially only the OCP and a few in- livery methods that would be sus- tion for the treatment of on- ternational NGOs who could en- tainable. AND CONTROL STRATEGIES

What was TDR’s role?

In 1994, TDR launched a multi- ly organize much more complex country study involving eight mul- traditional community activities ti-disciplinary research teams very effectively. This led to the from five African countries to idea of community-directed treat- evaluate and further develop ment in which the community methods for community-based itself would be in charge of the ivermectin delivery. Early in the design and implementation of study, the researchers discovered ivermectin treatment. This con- that there was little active com- cept was tested in the second munity involvement in the ‘com- phase of the study through a munity-based’ approaches, and large randomized comparison in that communities had virtually no 272 communities of true 'com- influence on how treatment was munity-directed' treatment ver- planned and executed. But social sus 'community-based' treatment scientists on the teams noted that (as designed for communities by these same communities routine- control programmes.)

What were the results?

It was clearly demonstrated that rected ivermectin treatment meetings of community repre- ComDT is feasible and effective. throughout the remaining en- sentatives and health workers Communities could effectively demic areas in Africa.” could significantly improve this plan and implement ivermectin The large-scale implementation and further enhance a positive at- treatment, and they achieved of ComDT produced important titude of health workers. The higher treatment coverage if they new challenges and APOC re- current research focus is on the were empowered to design and quested TDR to help strengthen ability of countries and health sys- implement treatment their own the evidence base for ComDT tems to support ComDT after way. It was concluded that and undertake research on criti- APOC/OCP and on the use of ComDT is likely to be sustainable cal implementation problems. ComDT for multi-disease inter- because of the commitment These included issues relating ventions. The effectiveness of demonstrated by community to the integration of ComDT in ComDT for the treatment of lym- leaders and community distribu- the health services and the sus- phatic filariasis has already been tors, the high degree of involve- tainability of ComDT after cessa- demonstrated in a multi-centre ment of communities, and their tion of APOC support. Follow-up study in Africa. ComDT achieved ability to recognize problems with studies showed that, although coverage of over 80%, as com- their distribution methods and ef- health workers initially had a neg- pared to 45% by the health fectively modify them. On the ba- ative attitude to active communi- services. In this study, the issue of sis of TDR’s work, ComDT was ty involvement in drug delivery, integration was addressed from adopted by OCP as its ivermectin their attitude became much more the start and ComDT was intro- delivery strategy and it became positive after experience with duced to the communities by the principal control strategy for ComDT. Poor communication the health services themselves. the APOC programme in 1996. and interaction between commu- ComDT is now also recom- The main objective of APOC is nity members and health workers mended for mass treatment for now “to establish effective and was also common but research lymphatic filariasis elimination in self-sustainable community-di- showed that local stakeholders Africa. NEW AND IMPROVED POLICIES, PREVENTION

Getting drugs into wide control use

Very few new drugs for tropical diseases Introduction reach the market The international pharmaceutical industry, with few excep- and, even if they tions, has shown little interest in drugs for tropical diseases do, there are huge due to market and government failures and enormous income inequities in access differences. Lack of money, lack of drugs, poor quality and to drugs between rich counterfeit drugs, prohibitive cost, incorrect use due to lack and poor countries. of training or lack of information, all lead to inaccessibility for the poor. There is a need to develop field-based drug research to determine optimum utilization and remotivate research and development for new drugs for the developing world, as TDR is attempting to do through forming partnerships between the public and private sectors and between the developed and developing worlds. This snippet highlights some examples of how TDR has helped bring new drugs into disease control use.

Why did TDR get involved? What was TDR’s role?

Because, even though a new drug TDR has helped bring a number er, Merck & Co. Inc., for the supply may be available, i.e. has reached of drugs into disease control use. of ivermectin, and with the On- the market, it may not be acces- Below are some examples: chocerciasis Control Programme sible to those who need it, for a To expand the use of (OCP) for provision of advice on variety of reasons. For instance, it artemether for disease control how to distribute and monitor the may be expensive to produce use for malaria,TDR negotiated a drug in Africa. Merck & Co. Inc. and hence to buy, so poor and preferential price for the public donated ivermectin for onchocer- marginalized populations who sector with the manufacturer, ciasis for ‘as long as necessary’. It need it cannot afford to buy it. Rhone-Poulenc Rorer Doma. A provided 92 million tablets in TDR, from its base within the collaborative agreement was 1999 alone through 29 countries. United Nations system, its long made with this company whereby To bring albendazole into dis- history of partnership with in- data from TDR-funded non-clini- ease control use for lymphatic fi- dustry, the donor and developing cal and clinical studies were ex- lariasis,TDR helped negotiate with country research and control changed for the preferential price. the manufacturer, Smith Kline communities, is in a strong posi- The necessary safety and efficacy Beecham (now GlaxoSmithKline), tion to act as a broker between data were completed by the who pledged, in 1998, to donate the different stakeholders. The manufacturer. albendazole to WHO for ‘use by aim is to make drugs accessible To bring ivermectin into disease governments and other collabo- to those who have the needs but control use for onchocerciasis, rating organizations until lymphat- not the means to reach the drugs TDR negotiated with the interna- ic filariasis is eliminated from the via the usual market mechanisms. tional pharmaceutical manufactur- world as a public health problem’. AND CONTROL STRATEGIES

To bring eflornithine into dis- Médecins sans Frontières (MSF), a ease control use for the gambi- non-governmental organization ense form of African trypanoso- that has made great efforts to miasis,TDR was involved in nego- contain Sleeping Sickness, helped tiations with the private and non- to search for the third party who governmental sectors.This drug is would manufacture eflornithine. very expensive to produce, but is Together, TDR and MSF ap- very much needed, particularly proached donors who, it was where resistance to arsenicals has hoped, would provide funds to become a problem. Eflornithine is guarantee production of eflor- now no longer manufactured, but nithine, initially for five years. the manufacturer, Hoechst Mari- on Roussel Inc., has granted WHO reference right to produce eflornithine. This will allow technology for production of the drug to be transferred to a third party, also in the private sector, who will manufacture eflornithine.

What were the results?

In 1999, the use of artemether This is the basis of the strategy for The search for potential manu- as intramuscular injection for elimination of lymphatic filariasis facturers of eflornithine had treatment of severe malaria was by 2020. Since the programme led, by January 2001, to the iden- expanded to more than 30 en- was initiated (2000), SmithKline tification of eight companies. demic countries and the drug was Beecham has provided 34 million One of these had produced a included (restricted use) in the tablets of albendazole through sample which was being chemi- WHO Model List of Essential WHO. WHO/TDR facilitated cally analysed, in January 2001, to Drugs. the procurement of 115 million see if it met purity specifications. Mass treatment of lymphatic tablets of DEC, and Merck and By February 2001, firm plans for filariasis consists of a single dose Co. Inc. provided ivermectin for production and supply of eflor- of two-drug treatment – of the Ghanaian, Nigerian and Tan- nithine were in sight. DEC plus albendazole,or zanian lymphatic filariasis pro- ivermectin plus albendazole. grammes. PARTNERSHIPS AND

PartnershipsPartnerships inin sciencescience

TDR is a global Introduction leader in fostering partnerships that Today there is an imbalance in generation of knowledge and generate new knowl- research funding: only 10% of global research funding is edge about tropical spent on diseases or conditions that account for 90% of the global disease burden (a situation known as diseases and in bring- the ‘10/90 gap’). TDR is about closing this ing researchers gap. In addition to looking at the physical from developing products, e.g. drugs, tools, guidelines, it is disease endemic in the scientific literature that the results countries into of TDR efforts in capacity building and the mainstream promotion of research in disease endem- of research to find ic countries can be found. solutions to the public health problems related to TDR’s target diseases.

Why did TDR get involved? What was TDR’s role?

TDR is a knowledge management TDR has a role as catalyst, facili- During the past decade,TDR en- and network organization, which tating the R&D agenda through gaged with 2631 new partners in manages the generation and ap- setting priorities, funding projects, 124 different countries. These plication of knowledge through and bringing together partners partners were engaged directly to linking and brokering the stake- who have the comparative ad- undertake research and develop- holders and processes needed for vantages required to make end- ment, build research capacity in fostering and applying new knowl- products become realities. TDR developing countries, develop re- edge to effectively combat tropi- has unique operational capabili- search tools, or to provide sup- cal diseases.TDR also has the goal ties which allow it to bring to- port and technical advice. of strengthening capacity in dis- gether the world’s leading re- ease endemic countries to un- searchers and product develop- dertake the research required for ers, from both public and private developing and implementing sectors and both developing and new and improved disease con- developed countries.These capa- trol approaches. TDR believes bilities allow TDR to fund and that knowledge is a crucial ele- manage, in an efficient, account- ment in health improvement, and able, and transparent way, a large that the attainment of self-re- number of research and product liance in research and develop- development projects as well as ment in disease endemic coun- the knowledge and capacity they tries is key to sustainability. generate. CAPACITY BUILDING

What were the results?

A Wellcome Trust study on international funding for malaria research in 1998 concluded that, of six major funding bodies and rel- ative to the financial investment of each, TDR had the highest number of acknowledgements per unit of investment, and over- Frequency of funding acknowledgements all the most funding acknowledgements; and that, according to citation in randomly selected papers citations to published papers, (Michaud 1998) TDR’s performance was in line TDR Other major Others with other top funding bodies. In Disease (% of total funders (% of total another Wellcome Trust study on papers) (top three) papers) malaria research capacity in African Africa,TDR came out top of the trypanosomiasis 51 NIH (USA) 15 list for all indicators used, includ- European Commission 15 Wellcome Trust 9 ing source of funding for African malaria research laboratories, and Chagas disease 30 CONICET (Venezuela) 39 master’s degree and PhD training FINEP (Brazil) 28 for African researchers. NIH (USA) 15 A Harvard University analysis Filariasis 27 ICMR (India) 38 revealed TDR to be the leading CNPq (Brazil) 8 funding source for research on Edna McConnell Clark Foundation 5 African trypanosomiasis, leishmaniasis, leprosy, malaria and Leishmaniasis 33 CNPq (Brazil) 32 onchocerciasis, ranking second NIH (USA) 6 for Chagas disease, filariasis and Leprosy 25 LEPRA (Malawi) 21 schistosomiasis. More than 83% NORAD (Norway) 14 of TDR funded papers were cit- SIDA (Sweden) 8 ed at least once, and frequently- Malaria 30 NIH (USA) 17 cited papers were not confined Wellcome Trust 12 to authors from industrialized USAID (USA) 11 countries – of the 24 most high- Onchocerciasis 39 NIH (USA) 28 ly cited papers in all subject ar- European Commission 24 eas, four were authored by peo- Wellcome Trust 10 ple from developing countries. Schistosomiasis 22 European Commission 23 This is a significant percentage – Edna McConnell Clark some 16% – when considered in Foundation 18 the light of the well-known bias CNPq (Brazil) 9 of English-speaking industrialized Note: country journals towards authors CNPq, Conselho Nacional de Desenvolvimento Científico e Technológico; from industrialized countries CONICET, Consejo Nacional de Investigaciones Científicas y Technológicas; (overall, less than 0.01% of arti- FINEP, Financiadora de Estudos e Projetos; ICMR, Indian Council of cles indexed in MedLine originat- Medical Research; LEPRA, Leprosy Relief Association Control Project; NIH, ed in developing countries). National Institutes of Health; NORAD, Norwegian Agency for International Development; SIDA, Swedish International Development Cooperation Agency; USAID, United States Agency for International Development. PARTNERSHIPS AND

Building research capacity in least developed countries

‘Tacit’ knowledge and skills are different from Introduction ‘codified’ knowledge as Studies have shown that up to 30% of African scientists are found e.g. in published lost to the brain drain. The brain drain not only has severe literature. Tacit knowl- implications for the ability to build and maintain a critical edge and skills are mass of tacit knowledge and skills in these countries, it also embodied in people means less research being done that is relevant to the prob- and are learnt through lems of the least developed countries. A major contributing actual training, e.g. in factor is the limited opportunities, after training, to conduct laboratories and meaningful research as national research funding is extreme- universities. Disease ly scarce and international funding is often biased towards endemic countries already established institutions. TDR’s highly customized, (DECs), in particular integrated, and seamless approach to capacity building and research funding represents one of the few mechanisms for the least developed, researchers from least developed countries to be involved in, are losing their tacit and for building a sustained basis for, research of local and knowledge as highly- international relevance. skilled researchers Partnerships at both the individual and institutional level, are finding employment networking and promoting equal opportunities, gender and elsewhere, often result- geographical balance among DEC researchers, constitute the ing in shifting research core of TDR’s approach to building research capacity. This away from advance- approach has proven highly effective in many countries ment of knowledge to where TDR continues to collaborate with scientists whose creation of wealth. research groups received early support from TDR. Many of these groups now participate in the global research agenda, from basic biological and social science to research into how new policies and strategies are best introduced into countries’ health systems. Many developing countries’ research and training centres are now also engaged in helping to build research capacity in other developing countries.

Why did TDR get involved?

Closing the global gap in research tries, are derived from the core identifying needs and developing and product development be- values on which TDR is founded. solutions to the public health tween the rich and the poor, and One of the two goals of the Pro- problems caused by neglected in- increased involvement of re- gramme is to increase self-re- fectious diseases that affect them. searchers from developing coun- liance in endemic countries for Building research capacity has CAPACITY BUILDING

been a major component of What was TDR’s role? TDR since its inception. Over the years, TDR has established managerial systems and ca- TDR’s research capability by facilitating a direct impact on pacity strengthening approaches strengthening activities have re- research and control. which can handle large numbers flected the changing capacities With its new strategy,TDR has es- of trainees and ensure appropri- and infrastructures in DECs. In tablished two main tracks in its ate re-entries and maintenance of TDR’s formative years, support approach to capacity building. a research base in home coun- concentrated on large-scale insti- One track is driven by the R&D tries. The dual role of TDR, as a tution strengthening, often involv- output, i.e. leading research insti- funding agency for capacity building the provision of crucial equip- tutions, from least as well as more ing as well as for actual conduct ment and support for multi-dis- advanced developing countries, of research and product develop- ease or cross-disciplinary re- are invited to compete for par- ment, forms the basis for its com- search projects.With the evolving ticipation in R&D work con- parative advantage as one of the scientific capacities and infrastruc- tributing directly to TDR’s R&D world’s lead organizations in re- tures in many DECs in the late agenda and to build capacities to search capacity building. 1980s, the emphasis shifted to a become more internationally balance of institution and individ- competitive.The other track is re- ual support where priority was served strictly for researchers given to human resource devel- from least developed countries opment. Research training grants and aims more broadly to lay sol- are awarded on a highly compet- id foundations for building future itive basis to applicants with fixed sustainable research capacities in employment in a relevant re- these countries. search or control position, there-

What was the impact?

TDR has supported over 1000 have similarly higher success rates search in developing countries. trainees from 416 research in receiving TDR R&D funding More importantly, there is a grow- groups and institutions drawn than non-TDR graduates (the ing ability of these countries to from 76 developing countries. TDR steering committee funding make use of this knowledge. From TDR is often considered unique averages being 58% and 30% TDR’s viewpoint, the result has among funding agencies in that respectively). been a new cadre of public health over 95% of its trainees return to TDR has played a significant role and scientific research leaders and their countries to continue work- in boosting overall research capa- specialists. Past TDR grantees now ing in their areas of specialty.TDR bilities in developing nations. Be- provide opportunities to train encourages applications from tween 1970 and 1985, the num- young scientists to develop re- women, and over one third of ber of skilled people engaged in search teams, and to promote funded individuals have been research in Africa rose by a factor partnerships. Former TDR trainees women.The majority of TDR PhD of 10 and funds for R&D in- and supported institutions now graduates (60%) have published creased 7-fold over the same pe- play pivotal roles in research as more in the post-grant period riod. In the past decade, there has well as in control and health pol- than the pre-grant period. TDR been an extraordinary growth of icy making, nationally, regionally, graduates have higher success scientific knowledge and tech- and internationally. rates than non-TDR graduates in niques with application to tropical applying for re-entry grants (57% disease research. Much of this versus 30%), and TDR graduates knowledge has come from re- PARTNERSHIPS AND

Technology transfer

TDR’s technology Introduction transfer initiatives aim to help advanced An excellent example of the initiatives in which technology developing countries has been transferred through TDR activities is the Thailand improve their own Tropical Diseases Research Programme (T-2). This programme, established in 1997, comprises an organization research and which promotes research into new product (drugs, vaccines, development (R&D) diagnostics) development and screening. TDR partners in capacities. this venture are the Thailand Research Fund, and the National Science and Technology Development Agency/National Center for Genetic Engineering and Biotechnology of Thailand (NSTDA/BIOTEC).

Why did TDR become involved?

conditions in tropical regions and to support research, more than the prospective poor return on sufficient patients infected by or investments.There was – and re- open to infection with target dis- mains – a need for transfer of eases, and a broad range of natu- technology to advance and pro- ral products which are sources of mote research and development potential new drugs and active capabilities for tropical diseases compounds. through collaborative activities. Furthermore, the cost of effective medicines is often out of reach for A profound need for new prod- healthcare programmes in many ucts for tropical diseases has long tropical regions, creating the need been recognized.TDR became in- for both discovery and develop- volved because the pace of emer- ment of new products for tropi- gence of drug resistance and con- cal diseases and mechanisms to sequent drug obsolescence, and help those most in need get ac- the rate at which therapeutic cess to whatever tools become agents were losing their effective- available. Technology transfer to ness, was not being countered by disease endemic countries might, current research.This is partly due for example, result in production to the lack of activity by agencies, of cheaper, and hence more ac- institutions and commercial en- cessible, medicines. terprises in both the public and Thailand is highly suited as a loca- private sectors in the West, tion because it boasts a corps of founded on the poor economic well-trained scientists, resources CAPACITY BUILDING

What was TDR’s role?

As a co-founder of T-2, and with ance and results and making rec- of high quality and reliable, and its expertise, experience and rep- ommendations for further action. therefore internationally valid. utation, TDR plays an important Within the T-2 consortium While TDR’s role is in providing role in overall programme man- arrangements, TDR is the instru- the important international con- agement. TDR orchestrates re- mental factor in building and context to facilitate linkages, the role search assistance to T-2 through solidating networks of re- of the Thai partners is in provid- its connections with universities searchers and entrepreneurs. ing the important Thailand-based and pharmaceutical companies, From this base,TDR has catalysed research context under which providing the important interna- research on its target diseases (T- T-2 operates, as well as in coor- tional context to facilitate linkages 2, amongst its other diseases, car- dination to convene, arrange and and promote 2-way information ries out research on malaria, cover the costs of all meetings of flow between Thai and foreign dengue, filariasis and tuberculo- the international advisory and expertise, and plays a role in the sis). Of special relevance,TDR has steering boards. evaluation of research perform- sponsored and conducted workshops on good clinical practice (GCP) and good laboratory practice (GLP).The implementation of these practices will ensure that the data produced from drug and vaccine development studies are

What were the results?

Within the first two years (1998- screened using a newly-devel- 99): oped and simplified method, • technology transfer had oc- with 985 returning positive an- curred through exchange of timalarial indicators. Some are Thai and foreign investigators being further evaluated. and training of investigators • researcher had developed in specialized fields (e.g. me- a PCR method to detect dicinal chemistry, screening of Wuchereria bancrofti in mos- biological activity) in Thailand quitos – which could be used and abroad. as a tool to monitor and eval- • and following the first uate the filariasis control pro- TDR/GLP workshop in Thai- gramme in Thailand. land, subsequent workshops • two special tuberculosis labo- had been conducted in-coun- ratories had been established. try by the original trainees. In one, more than 2200 sam- • a new antimalarial was under ples of pure compounds and development – a combination natural products had been of an artemisinin derivative screened for anti-TB activity. In plus mefloquine. the other, research is ongoing • in a high-throughput screening on characterization of strains system, 6424 samples of Thai of Mycobacterium tuberculosis natural products and synthetic in Thailand (1567 strains col- compounds had been lected in first 2 years). PARTNERSHIPS AND

SchistosomiasisSchistosomiasis controlcontrol capacitycapacity inin ChinaChina

China is now well on the way to producing Introduction a sizeable body of Research was a fundamental part of the overall effort for high-class research control of schistosomiasis in China, supported by a World on schistosomiasis. bank loan. A Joint Research Management Committee (JRMC) Research institutions was set up to administer the research programme, to which have been strength- TDR contributed by supporting the participation of four advisors – two staff members and two outside experts. The JRMC ened, experienced strategy was to ensure cost-effectiveness of the chemother- scientists established, apy programme, improve health education, encourage devel- and a much improved opment and implementation of serologic diagnostic tech- network for schistoso- niques, develop new approaches to schistosomiasis control, miasis control in and help raise the quality of management. In 1995, activi- China developed. ties became concentrated on surveillance and treatment, with a strong focus on diagnostic techniques, geographical information systems (GIS), prevention of schistosomiasis by application of new drugs (artemether), and cost-effective control management in different types of endemic areas.

What was Why did TDR become involved? TDR’s role?

TDR became involved because of were in keeping with the TDR Especially important was TDR’s its interest in promoting research, goals of reducing morbidity role in advising on, assessing and research capacity building and caused by neglected tropical dis- providing systems for managing linking closely with control activi- eases, and increasing the self- research proposals and projects. ties. JRMC was seeking solutions reliance of endemic countries in By sponsoring expert advisors to through research and the speed- research. The end products of the JRMC, 245 projects were ing up of implementation of new JRMC, like those of TDR, are so- selected for support out of more findings in the field, a focus of lutions to public health problems. than 800 submitted for consider- TDR. It functioned as the re- ation, 6 workshops were organ- search arm of the consolidated ized, and 23 young scientists were effort to eliminate schistosomia- trained abroad. In using its oper- sis as a public health problem in ational capability of acting as a China, organizing nationwide co- catalyst, TDR provided sustained operative research on common input to the mobilizing and galva- problems for policy, management nizing of scientists working in and methods in schistosomiasis academic institutions and staff di- control. Thus the JRMC goals rectly occupied in control activities. CAPACITY BUILDING

What were the results?

In all, during the seven years, 278 • techniques for rapid evaluation theses were published, 25 proj- of schistosomiasis in lake and ects were awarded prizes, and marshland regions, and the na- 7 projects generated patents. tional schistosomiasis surveys The development of novel ap- for evaluation of the control proaches to chemotherapy project after the first five years. turned out to be the field where • development, application and the most important discoveries evaluation of a rapid diagnostic were made. Several new control kit for the detection of Schisto- tools were produced which may somiasis japonicum circulating improve future control approach- antigen. es. Some notable achievements • the development of a new mol- were: luscicide (awarded a patent). • use of artemisinin derivatives in The overall impact on endemici- prevention of schistosomiasis – ty and, particularly, on the intensi- a novel application of arte- ty of disease due to schistosomi- misinin derivatives (otherwise asis during the seven years was used for malaria) which is favourable. In one province, schis- probably the most important tosomiasis was declared eradicat- discovery in the field of schis- ed and, in others, the number of tosomiasis in recent years. villages classified as endemic was • cost-benefit analyses of various reduced by 20-50%. strategies, e.g. of targeted As schistosomiasis is now ap- chemotherapy compared to proaching elimination as a public mass chemotherapy in heavily health problem in may areas in endemic areas – targeted China, the researchers who were chemotherapy was found to be trained and given opportunities cost-effective in highly endem- under this programme are now ic areas. moving on to apply their skills • advances in immunodiagnosis, and knowledge to solve other including the establishment of public health problems. a national reference centre with provincial serum bank. • implementation of a new technique to control snails spreading with the river irrigation systems (a patent granted on this technique). • improved methods for the surveillance of cercariae-infected water – a new and better method was developed which is now taught in training cours- es and used in endemic areas of several provinces. • application and evaluation of school-based health education emphasizing the risk for schistosomiasis. DISSEMINATION OF INFORMATION, GUIDE

Internet communications

Access to, and Introduction exchange of, information has increasingly Since the invention of the World Wide Web, a revolution in become a determinant the way information and data are communicated and shared for progress in science. has taken place. In the early 1990s, TDR was among the first in the area of health research to exploit the potential of the Internet and World Wide Web. In 1993, TDR established an email listserv, the tdr-scientists list, and a couple of years later, TDR published its first web page. Today, with some 1000 pages and 350 links to external websites, the TDR website forms the backbone of TDR's electronic communications activities, which also include digital photography, CD-ROMs, video and television. Continually evolving using the latest and most appropriate technologies, the website represents a major vehicle through which TDR reaches its target audiences throughout the world, and through which researchers can reach each other.

Why did TDR become involved?

As a network and knowledge site (and other) CD-ROMs, to- management organization, com- gether with support of initiatives munication is an essential com- to improve Internet connectivity, ponent of TDR's work. Dissemi- aim to narrow the information nating and providing access to sci- gap for TDR scientists. entific and technical information With respect to access to,and ex- on target diseases, new control change of, information relevant to tools and methods, best practices, research in tropical diseases,TDR and research needs and results, is aims to become a world-leading an important part of TDR's ob- hub. jectives. Provision of information on TDR's progress, transparency What was TDR’s role? in operations, and advocacy to raise awareness and draw atten- tion to, and support for, TDR's Using its full range of in-house sci- duction of material on all aspects work, are also of critical impor- entific, communications, and in- of its target diseases and related tance. formation technology expertise, research activities. TDR takes Although the so-called 'digital di- and working closely with special- complex, highly specific and often vide' still puts researchers from ists in its co-sponsoring agencies, jargon-filled scientific research da- developing countries at a disad- i.e. UNDP,World Bank and WHO, ta, and reworks and repackages it vantage as compared to their col- TDR has remained at the fore- in a format easily digestible and leagues from industrialized na- front of electronic publishing with understandable for dissemination tions, TDR's production of web- regard to development and pro- via the Internet. In addition, TDR LINES, INSTRUMENTS AND ADVICE

TDR website Pageviews per month by user category (in 2000) 30000

25000

20000 Industrialized countries 15000 Unresolved/Unknow* . net* 10000 Developing countries 5000 Non-profit*

. int* 0 April May June July August Sept. October Nov Dec * country of origin unknow

maintains a web-based network- What are the results so far? ing area on its website, with links to over 350 related external websites and discussion groups – in- The TDR website and listserv contact and information ex- formation reported by sub- have become important media change between researchers scribers to the tdr-scientists email through which TDR disseminates (in the pipeline). list and thus of interest to the and exchanges information. Serv- Key information is simultaneously wider tropical disease research ing initially as an outlet for pro- posted on both the website and community.These pages have re- viding information on grants, listserv, and coordinated use of ceived several awards for a 'clean research priorities and deadlines other electronic and traditional bill of health', and are among the for proposals (including online publishing methods ensures that most frequently visited pages on application forms), the website TDR meets the needs of those the TDR website. underwent a major redesign in with zero, poor or unreliable con- Since 1994,TDR's support of par- June 1999 to also include: nectivity. asite genome projects have • General information on TDR: In January 2001, the TDR website helped to establish databases and strategy, organization, gover- received approximately 70 000 blast servers, which are all now nance, resources and outcomes pageviews – almost twice as accessible via the Internet (see • Interactive versions of TDR's many as the previous year. Parasite Genome snippet). Programme Report and re- Over a 5 month period in 1999, search highlights 250 feedback emails were re- • A complete set of TDR's Final ceived via the site from 60 differ- Report Series presenting lead- ent countries. ing examples of TDR-support- With only 50 subscribers at the ed projects outset, the tdr-scientists list now • Multimedia resources, including has close to 2000 participants, TDR website: videos, and searchable access 35% of whom are developing to the TDR image library – country scientists. At least 8% of www.who.int/tdr a unique catalogue of over visits to the TDR website originate tdr-scientists list: 12 000 images from developing countries. Many To subscribe, e-mail to • A complete listing of TDR pub- of those visits from unresolved or [email protected] lications and reports available unidentified locations (61% of the and type the following in to download total) may also be from develop- the body of the message: • Latest news from TDR ing countries. New content is subscribe tdr-scientists • Web-based discussion forums posted to the website and the list- and trainee profiles to facilitate serv on an almost daily basis. DISSEMINATION OF INFORMATION, GUIDE

Guidelines to good practices

‘Good practices’ in preclinical and Introduction clinical trials of new Use of standard practices ensures that drug/vaccine devel- drugs and vaccines opment studies are up to acceptable standards. If disease have been used as a endemic countries are to play a greater role in drug and vac- standard by drug cine development, there is a need to ensure that good prac- regulatory authorities tices are followed in order that data produced are high qual- in industrialized ity, reproducible and acceptable to drug registration authorities everywhere. A developing country will then be able to countries for over market the products it has developed in the rest of the 20 years. world. All data obtained from preclinical and clinical trials are ultimately used by regulators to authorize marketing of the end product. Preclinical development of a compound, during which its safety is evaluated and the data obtained used to make decisions regarding first use of the product in human, involves examining the compounds in vitro and in animal models. If results from preclinical safety studies are satis- factory, the compound enters the clinical stages of development, in which it is examined in human for safety and efficacy. Apart from complying with international standards of practice, all biomedical research has to comply with established international guidelines concerning ethical and scientific review of the research, including providing patients with full information so that their consent to participate is informed.

Why did TDR become involved?

TDR became more involved in non-existent in disease endemic medical research do exist, they drug and vaccine development countries. So TDR began to sup- are at a theoretical level, and there for tropical diseases as the phar- port transfer of good practices was a need for guidelines that maceutical industry became less to disease endemic countries were practical (operational). The interested in this therapeutic area through training workshops and TDR guidelines will enable local and the need for disease endem- production of guidelines. ethics committees to develop ic countries to play a greater role TDR produced ethics guidelines their own specific review proce- in drug and vaccine development in an attempt to begin the process dures needed to ensure the pa- became evident. When TDR be- of strengthening ethical review in tient is not exploited. Implement- gan to promote good practices biomedical research in disease en- ing the standard informed con- (1999), the facilities and expertise demic countries. Although inter- sent procedures – whereby each necessary for implementation of national ethics guidelines and patient receives an explanation of these practices were virtually standards for carrying out bio- what the trial is about and gives LINES, INSTRUMENTS AND ADVICE

his/her consent to take part in the What were the results? trial - presents one of the biggest difficulties in conducting clinical trials in developing countries. In Following initial GLP workshops Western Pacific (FERCAP) coun- fact, few patients can fully under- in the different regions, the train- tries, Foro Latino Americano de stand all the details about the ing has become self-replicating. Comités de Ética in investigación study they are participating in, and Some of the original participants en Salud (Latin American Forum careful review by the ethics com- have conducted similar work- of Ethics Committees in Health mittee is one of the most effec- shops in their home countries to Research - FLACEIS), Pan African tive measures for this. help build up the needed capaci- Bioethics Initiative (PABIN). TDR became involved in the ty for conducting preclinical trials An annual course in research transfer of good practices be- according to good practices. ethics is now being offered by cause of its comparative advan- TDR has developed guidelines Thammasat University,Thailand, as tage of being able to draw on the (standard operating procedures) part of its regular activities. This expertise of the global scientific for clinical investigators, a GLP will enable Masters and PhD community in both public and pri- training manual, and is developing training in research ethics. vate sectors. Using this to advan- a GLP handbook to be used as a tage, the TDR guidelines were de- reference quality document in veloped in partnership with the disease endemic countries. As a world’s best experts in drug de- spin-off, a document to be used velopment. The good practice in areas of research that are not guidelines fulfil the need for qual- currently regulated (e.g. basic re- ity control in research. search, discovery studies, proof- of-principle studies, studies to establish pharmacodynamics effect and mechanisms of action) is also being developed by TDR. Demand for the good practice What was and ethics guidelines from the TDR’s role? TDR documentation center has been brisk. News of the GLP workshops, in particular, led to a TDR’s role was to convene meet- significant amount of interest – Partners ings of experts, prepare guide- judged by number of enquiries • Joint United Nations lines, and organize training work- from interested readers of the Programme on HIV/AIDS shops in disease endemic coun- TDR newsletter. As well, the (UNAIDS) tries run by experts, in order to ethics guidelines have been wide- • The pharmaceutical support training in good prac- ly distributed; within six months of industry (including Aventis tices, produce guidelines to good publication they were available in Pasteur; SmithKline practices, and help in implemen- ten languages (English, French, Beecham Biologicals; tation of these guidelines. The German, Laotian, Filipino, Russian, ASTA Medica) workshops have been jointly Spanish,Thai,Turkish,Vietnamese), • Ministry of Public Health, Thailand sponsored by TDR and its indus- the translations having been fi- • Organisation for Economic trial partners [see list].TDR’s op- nanced by various intergovern- Cooperation and erational capability in forming mental agencies, governments Development (OECD) global partnerships between and industry. • Regulatory authorities public and private sectors has Another result of the interest in (IKS, Intercantonal been important in this work. ethics issues was that, to foster Office for the Control of TDR has also set up monitoring improved understanding and im- Medicines, Switzerland; systems for clinical trials and has plementation of ethical review of FDA, Food & Drug Administration, USA) thoroughly trained clinical moni- biomedical research, different fo- • Scientists from disease tors in disease endemic countries ra have been set up: the Forum endemic countries around the world. on Ethics Committees in Asia and References

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New drugs brought to registration Strengthening health research in the developing world: malaria research capacity in Africa. The Wellcome Trust for 1 Pécoul, B. et. al. (1999) Access to essential drugs in the Multilateral Initiative on Malaria, London, (1999). poor countries: A lost battle? Journal of the American Medical Association, 281(4): 361-367 Schistosomiasis control capacity in China Xiao, S. et al. (2000) Preventive effect of artemether in experimental animals infected with Schistosoma mansoni. Yuan, H.C., et.al. (2000) The 1992-1999 World Bank Parasitology International, 49: 19-24 Schistosomiasis Research Initiative in China: Outcome and perspectives. Parasitol. Int. 49(3):195-207 Andrade, A.L.S. et. al. (1996) Randomized trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. The Lancet, 348: 1407-1413 Guidelines to good practices Politi, C. et. al. (1995) Cost-effectiveness analysis of TDR (2000) Operational guidelines for ethics committees alternative treatments of African gambiense trypanosomi- that review biomedical research. (TDR/PRD/ETHICS/2000.1) asis in Uganda. Health Economics, 4: 273-287 TDR (2000) Standard operating procedures for clinical Reich. M.R. (2000) The global drug gap. Science, investigators. (TDR/TDP/SOP/99.1) 287: 1979-1981. TDR (2000) Good laboratory practice training manual. (TDR/PRD/GLP/00.2) Getting drugs into wide control use Pécoul, B. et. al. (1999) Access to essential drugs in poor countries: A lost battle? Journal of the American Medical Association, 281(4): 361-367 Reich. M.R. (2000) The global drug gap. Science, 287: 1979-1981. WHO/TDR Avenue Appia 20 1211 Geneva 27 Switzerland Tel: (+41) 22-791-3725 Fax: (+41) 22-791-4854 E-mail: [email protected] Web: www.who.int/tdr