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ANNUAL REPORT 2009
TDR BUSINESS LINE 6
Drug development and evaluationfor helminths and other
neglected tropical diseases
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Copyright World Health Organization on behalf of the Special Programme for Research and Training in Tropical Diseases 2010
All rights reserved.
The use of content from this health information product for all non-commercial education, training and information purposes is en-
couraged, including translation, quotation and reproduction, in any medium, but the content must not be changed and full acknowl-
edgement of the source must be clearly stated. A copy of any resulting product with such content should be sent to TDR, World Health
Organization, Avenue Appia, 1211 Geneva 27, Switzerland. TDR is a World Health Organization (WHO) executed UNICEF/UNDP/World
Bank/World Health Organization Special Programme for Research and Training in Tropical Diseases.
The use of any information or content whatsoever from it for publicity or advertising, or for any commercial or income-generating
purpose, is strictly prohibited. No elements of this information product, in part or in whole, may be used to promote any specific indi-
vidual, entity or product, in any manner whatsoever.
The designations employed and the presentation of material in this health information product, including maps and other illustra-
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Mention or depiction of any specific product or commercial enterprise does not imply endorsement or recommendation by WHO,
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The views expressed in this health information product are those of the authors and do not necessarily reflect those of WHO, including
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health information product.
Design: Lisa Schwarb Layout: Bruno Duret
Cover Pictures: WHO/TDR/Kuesel. Photo caption: Before (left) and after (right) construction of a clinical trial centre in Butembo,
Nord-Kivu, Democratic Republic of the CongoPrinted by the WHO Document Production Services, Geneva, Switzerland
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Table of contents
List of tablesTable 1. Definition of terms .......................................................................................................................5
Table 2. HNR portfolio composition in 2009 by disease and strategic objectives ......................................14
Table 3. HNR portfolio planned for 2010 by disease and strategic objectives ...........................................15
Table 4. HNR projects, end products and expected outcomes .................................................................. 16
Table 5. Overview of clinical studies financed and managed by HNR in 2009 .........................................20
Table 6. Overview of capacity building conducted by HNR in 2009 ........................................................21
Table 7. Financial implementation 20082009 ........................................................................................22
Table 8. Expenditures by objective-disease matrix defined by HNR SAC 2009(Provisional as of data in GSM on 31 December 2009) ................................................................ 22
Table 9. Approved budget 20102011 ..................................................................................................... 24
Table 10. New projects initiated by HNR in 2009 ...................................................................................... 25Table 11. Progress and key achievements ................................................................................................... 26
TDR/BL6.10
List of abbreviations .........................................................................................................................4
Overview and highlights ................................................................................................................7
Background .............................................................................................................................................7
Strategic objectives ..................................................................................................................................7
Key activities in 2009 ..............................................................................................................................7Collaborations and leverage ...................................................................................................................10
1. Context, strategic objectives and framework ............................................................11
1.1 Context ...........................................................................................................................................11
1.2 Strategic objectives .........................................................................................................................12
1.3 Strategic framework ........................................................................................................................12
2. Key stakeholders, roles and responsibilities ................................................................20
3. Implementation plan 20082013 and progress ..........................................................21
3.1 Scope of activities in 20082009 ....................................................................................................21
3.2 Plan, progress and key milestones ...................................................................................................27
4. Leverage and contribution to empowerment and stewardship .........................404.1 Leverage .........................................................................................................................................40
4.2 Contribution to overall capacity building and stewardship activities ..............................................40
5. Critical issues and suggested solutions ...........................................................................41
6. Annexes............................................................................................................................................42
6.1 Overview of Moxidectin Development Plan and Status ...................................................................42
6.2 List of publications from HNR-funded or HNR-managed research ..................................................43
6.3 SAC membership ............................................................................................................................44
6.4 HNR projects, end products and expected outcomes .....................................................................45
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List of abbreviations
ALB Albendazole
ANC Antenatal clinic
APOC African Programme forOnchocerciasis Control
APW Agreement for Performance of Work
BENEFIT Benznidazole Evaluation ForInterrupting Trypanosomiasis
BL6 (HNR) Drug Development and Evaluation forNeglected Tropical Diseases
CD Chagas disease
CDI Community directed interventions
CDTI Community directed treatment withivermectin
CIR Community based interventions
CL Cutaneous leishmaniasis
DEC Diethylcarbamazine
DENCO Dengue control clinical study
DNDi Drugs for Neglected Diseasesinitiative
DQR Quality assured diagnostics
EC Ethics committee
EMEA European Medicines Agency
FDA Food and Drug Administration
FIND Foundation for Innovative Diagnostics
GCLP Good Clinical Laboratory Practice GCP Good Clinical Practice
GPELF Global Programme to EliminateLymphatic Filariasis
HAT Human African trypanosomiasis
HNR Drug Development and Evaluation forNeglected Tropical Diseases (BL6)
IV Intravenous
IVM Ivermectin
LF Lymphatic filariasis
MDA Mass drug administration
MMV Medicines for Malaria Venture
MoH Ministry of Health
MPR Anti-Malarial Policy & Access
NTD Neglected tropical disease
OCRC Onchocerciasis ChemotherapyResearch Centre
O.v. Onchocerca volvulus
OXQ Oxamniquine
PCR Polymerase chain reaction
PZQ Praziquantel
R&D Research and development
SAC Strategic and Scientific AdvisoryCommittee
SAE Serious adverse events
SoP Standard operating procedure
SPT Special Project Team advisorycommittee for projects requiringspecial expertise and/or more intenseongoing involvement of externalexperts than can be provided by theSAC (SPTs are in place for moxidectindevelopment, ivermectin responsemarkers research and Chagas diseaseprojects)
STAC Scientific and Technical AdvisoryCommittee
STH Soil transmitted helminths
TCC Technical Consultative Committee
TDR Special Programme for Research andTraining in Tropical Diseases
VL Visceral leishmaniasis
VLR Visceral leishmaniasis elimination
WHO World Health Organization
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Table 1. DEFINITION OF TERMS
Biomarker A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes,
pathogenic processes, or pharmacologic responses to a therapeutic intervention (Biomarkers Definitions
Working Group 1998).
Development Studies on the pharmacokinetics, safety and efficacy of a drug or drug combinations in humans aimed at
determining whether the drug or drug combination studied has the clinical target product profile required
for submission of a dossier for a decision on use of the drug or drug combination outside clinical trials (via
registration and/or recommendation of expert committees).
Development track
decision
Decision to initiate the studies required for a decision to conduct the first study in humans.
This decision includes recommendations on the types of studies required before the clinical studies for the
targeted indication can be initiated. The types of non-clinical and clinical safety studies required will depend
on the development and regulatory history of the drug candidate or combination of drug candidates.
Lead Compound efficacious in disease animal model with no overt toxicity and with characteristics potentiallysuitable for cost-effective scale-up.
Lead optimized Optimized lead compound with in vitro and in vivo activity, pharmacokinetic and toxicity profile potenti-
ally consistent with target product profile, and amenable to cost-effective scale-up of manufacturing can
be evaluated for development track decision.
Pharmaco-
epidemiology
The study of the use and effects of drugs in large numbers of people. [The importance of pharmacovi-
gilance. Safety monitoring of medicinal products, WHO 2002 (http://www.who.int/medicinedocs/collect/
edmweb/pdf/s4893e/s4893e.pdf)]
Pharmacology Science of drugs, including their composition/formulation, uses, pharmacokinetics, pharmacodynamics,
pharmacotherapeutics and toxicology
Pharmaco-surveillance
Regular monitoring of medications in real clinical practice for benefits and harms ( http://www.hc-sc.gc.ca/hcs-sss/pharma/nps-snpp/securit/guide_gloss-eng.php )
Pharmaco-
vigilance
The science and activities relating to the detection, assessment, understanding and prevention of adverse
effects or any other drug related problems Specific aims are to:
improve patient care and safety in relation to the use of medicines and all medical and paramedical
interventions;
improve public health and safety in relation to the use of medicines,
contribute to the assessment of benefit, harm, effectiveness and risk of medicines;
encouraging their safe, rational and more effective (including cost-effective) use; and
promote understanding, education and clinical training in pharmacovigilance and its effective
communication to the public.
[The importance of pharmacovigilance. Safety monitoring of medicinal products, WHO 2002 (http://www.
who.int/medicinedocs/collect/edmweb/pdf/s4893e/s4893e.pdf)]
All scientific and data gathering activities relating to the detection, assessment, and unders-
tanding of adverse events (FDA Guidance for Industry Good Pharmacovigilance Practices and
Pharmacoepidemiologic Assessment, March 2005, http://www.fda.gov/Cder/guidance/6359OCC.pdf)
For guidelines, see :
EMEA: http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-9/pdf/vol9a_09-2008.pdf
FDA: http://www.fda.gov/Cder/guidance/6359OCC.pdf
ICH: http://www.ich.org/LOB/media/MEDIA1195.pdf
Pre-development Non-clinical safety studies required (e.g. by regulatory authorities) for a decision to conduct the first study
in humans.
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Risk management Iterative process of (1) assessing a products benefit-risk balance, (2) developing and implementing tools
to minimize its risks while preserving its benefits, (3) evaluating tool effectiveness and reassessing the
benefit-risk balance, and (4) making adjustments, as appropriate, to the risk minimization tools to furtherimprove the benefit-risk balance. [(USA) Food and Drug Administration. Guidance for Industry Good
Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, March 2005 (http://fda.gov/Cder/
guidance/6359OCC.pdf)].
Risk management
plan
EMEA terminology: Consists of safety specifications, a pharmacovigilance plan, an evaluation of the need
for risk minimization activities and, if there is a need for additional (i.e. non-routine pharmacovigilance
practices) risk minimization activities, a risk management plan..
Synergy In contrast to the classical definition that includes the concept that the whole is greater than the sum
of the individual parts, synergy is used here to refer to collaboration between different units within
TDR which is expected to yield a better result or a more efficiently obtained result than if each unit was
pursuing the work separately.
Target product
profile
Summary of pharmaceutical, efficacy and safety properties a drug or drug combination requires for its
intended indication.
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Overview and highlights
Background
Neglected tropical diseases (NTDs) generate
morbidity and mortality in poverty-stricken
populations. They are regarded as a public health
priority for the World Health Organization (WHO).The WHO strategy includes:
1. Innovative and Intensified Disease Management
for diseases for which cost-effective control
interventions do not exist for wide-scale use (the
so-called tool-deficient diseases).
2. Preventive Chemotherapy and Transmission
Control which uses available drugs often
distributed to populations in combination to
prevent morbidity and/or reduce transmission
(the so-called tool-ready diseases)In either case, few drugs are available and these
are under-researched in general there is little
information on their mechanisms of action, and
their dosage regimens are based on insufficient
pharmacokinetic and pharmacodynamic data.
Furthermore, their extended use carries the risk
of drug resistance developing. Therefore, new
or improved drugs and more knowledge of the
pharmacology and the effects of the use of those
currently available is required to support both
strategies.
Strategic objectives
These considerations have informed the
definition of the strategic objectives of HNR (drug
development and evaluation for neglected tropical
disease BL6):
(1) Development, registration and field evaluation
of new drugs, and
(2) Generation of evidence to optimize the use of
available drugs for NTDs.
Key activities in 2009
Refinement of scope and portfolio:
Following the recommendations of the TDR
Scientific and Technical Advisory Committee
(STAC) in 2009, (see section 6.4), the scope and
portfolio of activities for the coming years were
redefined by the HNR Strategic and Scientific
Advisory Committee (SAC) with input from the
WHO/Neglected Tropical Diseases department and
other key partners to cover two specific objectives:
1. Development, registration and field evaluation of
new drugs for NTDs including identification ofsuitable development candidates and initiation of
development (or fostering the development) of
selected candidates.
2. Generation of evidence for improved use of
currently available drugs for NTDs:
a. Pharmacology and improved use of current
drugs;
b. Pharmaco-epidemiology in support of disease
control;
c. Markers and methods for evaluation of
treatment effects.
Highlights of current activities
The final data of three studies became available in
2009:
Initial lymph node and vessel pathology
can be reversed if lymphatic filariasis (LF) is
treated in childhood with a combination of
diethylcarbamazine plus albendazole. The
first-ever study in children with parasitological
or immunological signs of Brugia malayiinfection
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conducted in India shows that mass drug
administration not only affects transmission,
but also has the potential to have effects ondevelopment of pathology.
Albendazole treatment is not effective in
reducing the risk of severe adverse reactions to
ivermectin in areas of co-endemicity of loiasis with
onchocerciasis and/or lymphatic filariasis. These
continue to slow down implementation of CDTI
(Community Directed Treatment with Ivermectin)
in onchocerciasis-loa loa co-endemic areas and
prevent the implementation of mass treatment for
LF in LF-onchocerciasis-loa loa co-endemic areas.
A four-country study in intestinal schistosomiasis
showed no differences in safety and efficacy
between 40 and 60 mg/kg of praziquantel. These
results support the current WHO policy dose
recommendation (40mg/kg).
Interim results of the ongoing 18-country validation
of the new evidence-based classification of dengue
disease show that physicians value its user-
friendliness and support for clinical management
and triage decisions particularly during disease
outbreaks. Three countries adopted the revisedclassification in their national guidelines.
The Phase 2 study of moxidectin in Ghana was
completed and the Phase 3 study initiated in the
Democratic Republic of the Congo and Liberia.
Further details are provided below by disease and
HNR objective.
1. Development, registration and
field evaluation of new drugs forNTDs
Onchocerciasis and lymphatic filariasis
Moxidectin development Phase 2 completed,
Phase 3 started.Ivermectin does not sterilize or
kill the adult O. volvulus. Transmission could be
interrupted with a macrofilaricidal or macrofilaria
sterilizing drug; such a drug must be safe for
mass treatment. HNR is evaluating moxidectin
(a drug from animal health) for this indication in
collaboration with Wyeth Pharmaceuticals (Pfizer
as of October 2009). In 2009, two studies managed
by HNR were active in addition to three other
pharmacology studies sponsored by the commercial
partner. The phase 2 trial completed post-treatmentfollow-up at the Onchocerciasis Chemotherapy
Research Centre (OCRC) in Hohoe, Ghana, in
November 2009. The pivotal phase 3 study (to enrol
1500 patients) was initiated in April 2009 in Liberia
and in December 2009 in two sites in the Democratic
Republic of the Congo. Initiation in Ghana is
awaiting national regulatory approval. In preparation
for the trial, three new clinical research centres in
the Democratic Republic of the Congo and Liberia
were built or renovated and equipped; the research
teams were trained in Good Clinical Practice (GCP)and Good Clinical Laboratory Practice (GCLP) at the
OCRC by the OCRC staff and TDR staff.
2. Generation of evidence for
improved use of currently
available drugs for NTDs
Onchocerciasis and lymphatic filariasis
Markers for evaluation of effect of ivermectin in
Onchocerca volvulus a north-south collaborativeproject stimulated and under evaluation.Control
of onchocerciasis depends on one single drug
(ivermectin) and is thus vulnerable to parasite
resistance. Should resistance occur, early detection
is currently not possible as its molecular basis is not
known and markers are not available. At the request
of the African Programme for Onchocerciasis
Control (APOC) in 2009, TDR engaged
investigators in Africa, Australia and Canada to
develop a joint proposal addressing both research
and capacity building needs. Four of five invitedproposals were received and are undergoing review
by the responsible Special Project Team.
Pharmacology and improved use of current
drugs for lymphatic filariasis trial shows clinical
benefits of treating children.The first-ever study
in children with parasitological or immunological
signs of Brugia malayiinfection completed the
planned follow-up period in 2009. The data showed
that diethylcarbamazine (DEC) and albendazole
given twice a year can reverse early lymph node and
vessel pathology. This provides proof-of-concept
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that administration of the drugs used by the Global
Programme to Eliminate Lymphatic Filariasis
can provide benefits beyond the interruption oftransmission (Shenoy et al. 2009).
Pharmacology and improved use of albendazole
treatment of loiasis tested albendazole regimens
cannot make ivermectin distribution safer in areas
of loiasis co-endemicity.CDTI for onchocerciasis
control cannot be deployed in the standard way
in areas where loiasis coexists because of toxic
reactions induced by ivermectins killing of loa loa
microfilariae. Ivermectin (IVM) could be safely
used if the loa loa parasite load were reduced. The
clinical study in Cameroon determining the effect
of two different albendazole treatment regimens
on loa loa microfilarial loads completed follow up
in 2009. The results show that neither regimen
can reduce loa loa microfilaraemia enough to
allow implementation of standard CDTI in loiasis
co-endemic areas.
Schistosomiasis
Pharmacology and improved use of
praziquantel in schistosomiasis trials support
WHO recommended regimen for intestinal
schistosomiasis.The dose of praziquantel for
treating intestinal schistosomiasis is not clearly
established. A multi-country study (800 subjects in
Brazil, Mauritania, the Philippines and the United
Republic of Tanzania) compared the safety and
efficacy of 40 versus 60 mg/kg of praziquantel.
In 2009 databases from the four trial sites were
harmonized and analysed both individually and
combined to generate an evidence-base for dosage
recommendations. There was no difference between
the two regimens and the current WHO policy
recommendation (40mg/kg) can be applied.
Leishmaniasis
Anthropometric database of patients with visceral
leishmaniasis (VL) multi-country database shows
that malnutrition is common and provides basis for
country-tailored drug cost calculations.The basic
demographic and anthropometric characteristics of
VL patients have not been investigated systematically.
In 2009, clinicians from south Asia, east Africa and
Brazil contributed nearly 30 000 patient data the
first database of this kind. Analysis of these data
showed marked differences across countries
and high proportions of malnourished patients,requiring control programmes to deliver nutritional
supplements. The database also allows general and
country-tailored estimates for drug and supplement
procurement and costs.
Clinical trial methods for cutaneous leishmaniasis
(CL) treatments experts design standardized
protocol. Studying treatment effects in CL is
complex. The lack of standardized methods makes
collation of study results and recommendations
difficult. In 2009 WHO/NTD and TDR/HNR
hosted a workshop of experts which developed astandardized protocol for CL.
Human African trypanosomiasis (HAT)
Improved use of eflornithine in stage 2 human
African trypanosomiasis (HAT) study completed
and analysis under way.Treatment for stage 2 HAT
by intravenous infusion of eflornithine 4 times a day
(each infusion taking 2 hours) is cumbersome and
difficult, particularly in remote areas. The NECT
(Nifurtimox-Eflornithine Combination Therapy)
phase 3 study in Uganda was conducted to evaluatean alternative treatment that would be as effective
as standard eflornithine while being cheaper, safer
and easier to administer. This study completed
follow-up in June 2009 and the database is under
preparation for analysis, aiming for a report by the
second quarter of 2010. This study will complement
existing information which supported the granting
of Essential Medicine status to NECT (filed by the
Drugs for Neglected Diseases initiative, DNDi).
Improved use of pentamidine for stage 1 HAT
trial recruiting.Current treatment of stage 1
HAT is by daily injections of pentamidine for one
week or more. This treatment is potentially toxic
and is impractical in field conditions; the drug
pharmacokinetics support a shorter treatment. The
ongoing study is comparing the safety and efficacy
of a three-day pentamidine regimen against the
standard seven-day regimen. In 2009, intensive
consultations with the WHO control programme
(NTD) and DNDi confirmed that this study is still a
priority for all stakeholders. An active partnership
was established with DNDi to speed-up and
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complete recruitment by the end of 2010. Due to
financial constraints and major investments in other
HAT-related programmes DNDi is unable to takepart in this study. HNR remains committed to the
study sites and patients and is identifying options
to complete the study in the most cost-effective and
responsible manner.
Chagas disease
Standardized PCR based method for clinical
diagnosis of Chagas disease method to be
tested in routine conditions.A multi-country
study generated a standardized methodology for
polymerase chain reaction (PCR) for diagnosis
of infection with T. cruzi. In 2009, plans for the
evaluation of this standardized method in different
settings and stages of infection were established
jointly with WHO/NTD and a preliminary proposal
was received and assessed by the SAC.
Dengue
New method for classification of dengue
new classification adopted by countries and
undergoing validation. In 2009, validation of
the new evidence-based classification of dengue
disease into three levels of severity was initiated
in 18 countries. Interim results show that dengue
physicians appreciate the new classification because
of user-friendliness, decision support for clinical
management and triage particularly during disease
outbreaks. Three countries adopted the revised
classification in their national guidelines.
Collaborations and leverage
Towards a TDR-wide approach to pharmaco-epidemiology.Pharmaco-epidemiology and
pharmacovigilance concern various business
lines (BLs) in TDR. In 2009, HNR initiated
discussions with the TDR research units for
Anti-malarial Policy and Access (MPR), Visceral
Leishmaniasis Elimination (VLR) and Community
Based Interventions (CIR) to evaluate strategies to
collect pharmaco-epidemiology/pharmacovigilance
information on drugs used for disease control.
Ongoing collaborations within and outside
WHO. Discussions with the Department ofNeglected Tropical Diseases (WHO/NTD), along
with the HNRs SAC, contributed to defining
the priority research agenda and identifying
specific research projects. HNR also has a long-
standing collaboration under a Memorandum of
Understanding with APOC.
HNR works with regional and country offices, as
well as in a project specific manner with researchers
in developing and developed countries, non-profit
organizations and the pharmaceutical industry.Leveraging contributions through interactions.
WHO/TDR support has attracted and leveraged
pharmaceutical company funding, free supplies
of study drugs and equipment, national control
programme support and infrastructure for clinical
trials, with the help and support of WHO country
and regional office staff.
Influencing high-level strategic framework.
In 2009, HNR contributed to the WHO-wide
interaction with the G8. Along with WHO/NTD,
HNR participated in activities which led to NTDs
being addressed in the final declaration of the G8
summit 2009 and various initiatives of the Italian
presidency to raise the profile of NTDs.
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For both groups of diseases, methods and systems
to monitor efficacy, safety, effectiveness and
potential emergence of resistance are needed.TDR is well positioned to undertake the work
required, based on its track record in drug
development and evaluation, its networks of
investigators and institutions and its history of
donor resourcing for this area of work.
1.2 Strategic objectives
The objectives defined in the 20082013 Business
Plan are:1. Development and registration of new drugs
for onchocerciasis, lymphatic filariasis,
schistosomiasis and other helminthiasis and field
evaluation of their effectiveness.
2. Generation of evidence for improved use of
currently available drugs to support disease
control, elimination or eradication strategies
for NTDs with emphasis on integrated disease
management or prophylactic chemotherapy
including:
Optimizing treatment regimens of available
drugs (efficacy and safety), including drug
combinations;
Assessing the efficacy and safety profiles of
drugs co-administered in mass distribution
programmes for different diseases;
Evaluating product safety and efficacy in
special populations (children and pregnant
women).
3. Development of products for other neglected
diseases when an opportunity emerges and no
other organization is available or is prepared to
undertake it.
In reviewing HNR activities, STAC in 2009
recommended to redefine the mission/objectives with
SAC input and to identify TDR/HNR added value (see
Section 6.4). A STAC-mandated special objective for
20092010 was thus to redefine HNR mission and
objectives with the end-product being a document
including a situation analysis, identifying research
needs in support of control and defining how HNRshould organize work to address those needs. HNR
objectives and priority activity areas were reviewed
in the context of the overall NTD control needs with
contributions from WHO/NTD and considering themandates of other relevant partners.
This situation analysis was completed in 2009,
and will lead to the completion in 2010 of a
modified business plan taking into account both
the priorities/areas of focus as per HNR SAC advice
and TDR and HNR financial and human resources.
Further information on the response to STAC
requests is provided in Section 6.4.
1.3 Strategic framework
The HNR SAC recommended to focus new HNR
activities as described below. An overview of the
foci of activities is provided in Table 2and Table 3
for 2009 and 2010, respectively.
Development, registration and
field evaluation of new drugs (for
short: New Drugs for NTDs)
For:
a) Onchocerciasis, lymphatic filariasis, soil-
transmitted helminthiasis, schistosomiasis,
foodborne trematodes and dengue.(These
diseases, unlike such diseases as visceral
leishmaniasis, African trypanosomiasis and
Chagas disease, do not have dedicated public
private partnerships to promote and support
drug development.)
b) Other neglected tropical diseases when the need
arises (e.g. diseases or indications not covered bydedicated organizations).
Activities include identification of drug
development candidates, transitioning from
pre-development into development, registration
and validation for use in the field, i.e. determination
of safety and effectiveness of the drugs in real-life
settings.
This work is conducted in partnership with
institutions from developed and developing
countries (private or public), including bio/pharmaceutical companies when relevant.
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HNRs work requires the building and strengthening
of local capacities and close interaction with disease
control programmes, health systems and regulatoryauthorities in developing countries.
The efficiency of the drug research and
development (R&D) process for the NTDs suffers
from the absence of reliable estimators of treatment
effects. We intend to contribute research on
methods and biomarkers to optimize and expedite
the process, hence potentially curtailing times and
costs of R&D (see 2c below).
Generation of evidence for
improved use of currentlyavailable drugs for NTDs (forshort: Treatment optimization &Biomarkers)
This activity supports the control strategies,
including both integrated, intensified disease
management (leishmaniasis, African and American
trypanosomiasis, dengue) and prophylactic
chemotherapy (helminths).
This activity is further subdivided into three areas:
a) Pharmacology and improved use of currentlyavailable drugs: The dosing regimens used for
treating many of the NTDs are often based on
incomplete pharmacological, efficacy and safety
information, and in many instances do not
address differences related to gender (especially
pregnancy), age or ethnicity.
Improved knowledge of the basic pharmacology
of these compounds is particularly important
as these drugs are often given concomitantly
for different diseases (drug mass administration
for integrated disease control) and may also becombined with other drugs for improved efficacy
(e.g. schistosomiasis, soil-transmitted helminths).
The availability of such information is essential to
optimize the use of currently available drugs, to
reduce the probability of resistance or to scale up
their use.
b) Pharmaco-epidemiology in support of disease
control: There is minimal information on
adherence (by prescribers and users) and
effects (efficacy, safety, effectiveness, resistance)
of interventions when used in real life. Thesedata are essential to optimize the impact of
interventions. However, methods (including
pharmacovigilance) to collect and analyse the
relevant data are imperfect and not adapted tothe conditions of use.
New paradigms need to be designed, tested and
optimized especially for community directed
interventions.
c) Markers and methods for evaluation of treatment
effects:Monitoring the effects of interventions is
particularly important when they are deployed
at the population level as resistance may occur.
Surrogate markers are also important to expedite
and optimize drug R&D. The additional benefit
will be improved case management with lesscumbersome tests for the patient.
Biomarkers for these diseases and standardized
methods for assessment of treatment effects for
many of these diseases need to be discovered
and validated.
Strategic considerations (including needs,
opportunities and resources) will guide the choice
of either of two management options: (i) direct
involvement management/funding of projects;
or (ii) playing a role in stimulating/fostering andproviding expertise in research projects.
The decision as to whether a new project should be
included in the HNR portfolio must weigh up the
resource implications, needs of ongoing projects
and the potential of innovative approaches to result
in a paradigm shift in NTD control strategies.
Furthermore, HNR needs to have sufficient
flexibility to address unanticipated control
programme issues.
Table 4presents an overview of all end-products
and expected outcomes for all ongoing projects
by strategic objective and disease. The portfolio
includes two clinical studies initiated before 2008
and not central to the current business line focus:
Clinical studies in Human African
Trypanosomiasis (NECT study). The follow-up
of the NECT study has been completed in 2009.
Final data are expected in 2010.
A three day pentamidine study; HNR will
continue to seek options towards completingenrolment as soon as possible.
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Table 2. HNR PORTFOLIO COMPOSITION IN 2009 BY DISEASE AND STRATEGIC OBJECTIVES
Diseaseactive in 2009
New drugsfor NTDs
Treatment optimization and biomarkers
Pharmacology& improved useof current drugs
Pharmaco-epidemiologyin support of
disease control
Markers & methodsfor evaluation oftreatment effects
Onchocerciasis/
LF
Moxidectin for Oncho
(Phase 3)
Drug develop-
ment candidate
identification
Eect of ALB on loa loa
microfilaremia
Eect of ALB+DEC on
LF in children
Pharmaco-
epidemiology/vigi-
lance in community
directed interventions
(Planning)
Markers of response
of O.v.to ivermectin
DEC patch for detec-
tion of O.v.infection
Schistosomiasis L-praziquantel
Drug develop-
ment candidate
identification
PZQ-OXQ combination
Praziquantel dose
comparison
Systematic reviews
(urinary & intestinal)
Dossiers on drugs in
use
STH Drug develop-
ment candidate
identification
Dossiers on drugs in
use
HAT Nifurtimox + eorni-
thine (NECT) for 2nd
stage
Pentamidine short
treatment for 1st stage
Chagas disease Benznidazole
(BENEFIT)
Validation of PCR
protocol for Chagas
diagnosis in the clinic
Leishmaniasis Standardization of
methods for Dx and
TxFU of cutaneous
leishmaniasis
Dengue Drug develop-
ment candidate
identification
Validation of new
disease classification
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Table 3. HNR PORTFOLIO PLANNED FOR 2010 BY DISEASE AND STRATEGIC OBJECTIVES
Diseaseactive in 2009
New drugsfor NTDs
Treatment optimization and biomarkers
Pharmacology& improved useof current drugs
Pharmaco-epidemiologyin support of
disease control
Markers & methodsfor evaluation oftreatment effects
Onchocerciasis/
LF
Moxidectin for Oncho
(Phase 3)
Drug develop-
ment candidate
identification
Eect of ALB+DEC on
LF in children
Pharmaco-
epidemiology/vigi-
lance in community
directed interventions
Markers of response
of O.v.to ivermectin
Schistosomiasis L-praziquantel
Drug develop-
ment candidate
identification
PZQ-OXQ combination
Systematic reviews
(urinary & intestinal)
Dossiers on drugs in
use
STH Drug develop-
ment candidate
identification
Dossiers on drugs in use
Improved benzimidazoles
HAT Nifurtimox+eornithine
(NECT) for 2nd stage
Pentamidine short
treatment for 1st stage
Chagas disease Benznidazole (BENEFIT) Validation of PCR
protocol for Chagas
diagnosis in the clinic
Biomarkers of treat-
ment effect
Leishmaniasis Standardization of
methods for Dx and
TxFU of cutaneous
leishmaniasis
Biomarkers of treat-
ment effect
Dengue Drug develop-
ment candidate
identification
Validation of new
disease classification
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BL strategic objectives Disease Project
1. New drugs for onchocerciasis, LF, STH,
schistosomiasis, foodborne trematodes
and dengue
Onchocerciasis/LF Moxidectin for onchocerciasis (and
lymphatic filariasis)
Schistosomiasis L-praziquantel for schistosomiasis
Helminths, dengue Drug development candidates for helminths
and dengue
2. Generation of evidence for improved
use of currently available drugs (treat-
ment optimization and biomarkers)
All Dossiers on drugs currently used for NTDs
2a. Pharmacology and improved use of
current drugs
LF Therapeutic eect of albendazole +
diethylcarbamazine (DEC) in children with
lymphatic filariasis
Onchocerciasis / LF Efficacy of albendazole in reducing loa loa
microfilaremia
Schistosomiasis
Combination of praziquantel and oxam-
niquine for schistosomiasis
Eective and safe dose of PZQ for Tx of
schistosomiasis
Systematic reviews in urinary and intestinal
schistosomiasis
Leishmaniasis Anthropometric database on patients with
visceral leishmaniasis from different endemic
areas
Chagas disease Benznidazole for the treatment of patients
in the late indeterminate or early chronic
phase of T. cruzi infection (BENEFIT)
Table 4. HNR PROJECTS, END PRODUCTS AND EXPECTED OUTCOMES
Projects initiated/planned in 2009 are indicated in italics
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End products Expected outcomes
(i) Clinical data from Phase 2 and 3 trials to assess
whether moxidectin meets target product profile for
registration (2011)
(ii) community study data on effect on onchocerciasis
transmission and safety during mass treatment (2015)
(i) Filing by manufacturer for registration
(ii) EMEA scientific opinion (Art 58)
(iii) registration by concerned endemic countries
(iv) distribution and use in control programmes
(v) recommendation on use by control programmes
(vi) change of onchocerciasis control objective from elimina-
tion of onchocerciasis as a public health problem to eradica-
tion of infection
Data to assess whether enantiopure L-praziquantel meets
target product profile for registration (2015)
(i) Filing by manufacturer for registration and/or list of essen-
tial drugs; (ii) registration/adoption by concerned endemic
countries.
Dossier on each potential candidate, expert evaluation, and
recommendation on transition into pre-clinical or clinical
development
Initiation of preclinical or clinical development, if indicated (with
or without HNR direct involvement)
(i) Compilation of non-clinical & clinical data publicly avail-
able for each drug used for treatment of NTDs (20102012)
(ii) Expert assessment for risks for flagging to disease
control programmes, design of studies to test and optimize
pharmaco-epidemiology/vigilance for NTDs, identification/
prioritization of HNR research (20102013)
Identification of research questions for treatment optimiza-
tion studies. Risk management plans established by WHO
disease control programmes and/or national disease control
programmes
Clinical evidence of the safety and efficacy in curing and
reversing lymphatic lesions in children infected with
Brugia malayi(20092012)
Lymphatic filariasis control programmes include cure of
infection and regression of early lymphatic lesions in children
(currently aiming only at interruption of transmission)
Proof of concept of efficacy of albendazole against loa loa
(2009)
Accelerated expansion of IMV use against onchocerciasis,
implementation of IV + ALB treatment in LF-loiasis co-
endemic areas
Data to assess the merits of drug combination for
schistosomiasis treatment (2011)
Adoption by schistosomiasis control programme as a means
to prevent emergence of drug resistance
Data to assess the safety and efficacy equivalence of 40
mg and 60 mg of praziquantel for Tx of schistosomiasis
(2009)
Use by national schistosomiasis control programmes for
decision on dose to be used
Evidence base for research and treatment policy recom-
mendations for schistosomiasis (2010)
Use of results to inform research priority setting and treat-
ment recommendations
Anthropometric database of patients with VL from all
endemic regions
Use of results to inform general and country-tailored drug
procurement strategies and complementary interventions (e.g.
nutritional)
Safety and efficacy (clearance of parasites -PCR) in the
chronic phase of T. cruzi infection in BENEFIT pilot (2010)
Contribute to a large multicentre study to demonstrate
reduction of risk of cardiac disease onset and progression in
T. cruziinfected individuals after Tx with benznidazole.
Change of treatment guidelines.
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BL strategic objectives Disease Project
2a. Pharmacology and improved use ofcurrent drugs (Type F)
Human Africantrypanosomiasis
Nifurtimox and eflornithine regimen(NECT) for the treatment of 2nd stage HAT
Three-day pentamidine treatment regimen
for 1st stage HAT
2b. Pharmaco-epidemiology in support
of disease control
Diseases controlled via
preventive chemotherapy
Testing and optimization of systems for
pharmaco-epidemiology/vigilance for com-
munity directed interventions
2c. Markers and methods of evaluation
of treatment effects
Onchocerciasis
Molecular markers of O. volvulus response
to ivermectin and tool for surveillance of
ivermectin response by control programmes
Transdermal delivery of diethylcarbam-
azine-citrate (DEC patch) as a diagnostic
tool for onchocerciasis
Chagas disease Standardized PCR for diagnosing Chagas
disease in the clinic
Dengue Revised dengue classification and updated
case management guide
Leishmaniasis Standardization of methods for diagnosisand evaluation of treatment effect
Projects initiated/planned in 2009 are indicated in italics
See also Section 6.6
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End products Expected outcomes
Data validating a 10-day regimen as providing efficacyequivalent to that of the standard 14-day eflornithine
treatment (2010)
Adoption by HAT control programmes, complement informa-tion which supported Essential Medicine status for NECT,
reduced workload for health systems, more acceptable
treatment for patients
Data validating the efficacy and safety of a three-day
regimen over the currently recommended seven-day
regimen (1Q 2013)
Adoption of a shorter pentamidine Tx course by control
programmes, improving compliance, reducing Tx related
complications and health system workload
New method(s) to collect safety, efficacy and resistance data
adapted to the conditions of use for community directed
intervention in countries where health systems are insuf-
ficiently developed
Provide control programmes with additional data to define
a surveillance plan and with methods to implement for
monitoring drug safety, efficacy and resistance. Contribute to a
better knowledge of drug effects (adverse events, efficacy and
resistance) and then a better use of the drug.
Three African laboratories with the infrastructure and
personnel capacity to participate in validation of molecular
markers (2011), Molecular markers indicative of the
response of O. volvulus to ivermectin (2012), Tool suitable for
large scale onchocerciasis control programme surveillance
(2014), Three African laboratories with the infrastructure
and personnel capacity to use the surveillance tool (2014)
Adoption of tool by onchocerciasis control programmes
Data from clinical and field studies showing that the DEC
patch can diagnose O. volvulus infection, is safe and suf-
ficiently specific (2008). Legal agreement between WHOand manufacturer on availability of DEC patch to WHO at
cost (2009)
Adoption by onchocerciasis control programmes as
epidemiological tool in data collection to assist in the
decision on when and where to stop ivermectin treatmentin areas with long-term onchocerciasis control and
surveillance post treatment discontinuation
Availability of DEC patch to control programmes at cost
Standardized and validated protocol for use of poly-
merase chain reaction (PCR) in the clinic to detect T. cruzi
Adoption as the standard for use in patient management,
blood screening, drug development and as reference meth-
odology for the development of new PCR kits
Clinical evidence to validate an improved dengue clas-
sification and case management guide (2010)
Adoption of a new dengue classification for better patient
identification and case management
A surrogate marker of treatment efficacy to reduce time forinitial determination of cure Improved case management; reduced clinical trial time andpossibly R&D time
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2. Key stakeholders,
roles and responsibilities
The main stakeholders are the WHO Department
for the Control of Neglected Tropical Diseases
(WHO/NTD), disease control programmes on
an international and national level, not-for-profit
organizations and industry.
The international disease control programmes
include: the African Programme for Onchocerciasis
Control (APOC) and the Global Programme for
the Elimination of Lymphatic Filariasis. National
stakeholders include control programmes for
schistosomiasis, dengue, Chagas disease, African
trypanosomiasis, onchocerciasis and lymphatic
filariasis. These stakeholders play a pivotal role in
highlighting the needs and gaps in tools, in linking
TDR with key national institutions such as national
drug regulatory agencies and researchers, and in
advocating for increased research funding.
HNR works closely with not-for-profit organizations
such as the Drugs for Neglected Diseases initiative
(DNDi), whose mandate is to discover and develop
new drugs for diseases caused by trypanosomatids
[visceral leishmaniasis (VL), human African
trypanosomiasis (HAT) and Chagas disease].
While avoiding duplications (HNR is not involved
in drug R&D for these diseases), we collaborate
and complement work, in particular to facilitate
R&D (e.g. research for biomarkers) and optimizeimplementation of new tools.
HNR depends very much on partnerships with the
pharmaceutical industry to accomplish product
development and regulatory approval. These
partners provide expertise, hands-on activities and
financial contributions.
Research centres and experts from developing and
developed countries are key partners as advisors,
disease experts, and in implementation of research
activities.
In addition to the donors who provide undesignated
funding to TDR as a whole, the African Programme
for Onchocerciasis Control, Bayer, the EUs Sixth
Framework Programme, GlaxoSmithKline, LTS
Lohmann Therapie-Systeme, sanofi-aventis, the
Wellcome Trust, The World Bank, and Wyeth
Pharmaceuticals (now Pfizer) contributed cash orin-kind support.
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3.1 Scope of activitiesin 20082009
Overview of portfolio
An overview of the portfolio has been providedin the context of the strategic framework where
Table 2shows an overview of HNR activities in
2009 by strategic objective and disease in the matrix
defined with the HNR SAC and Table 3shows the
scope of activities planned for 2010 in line with
STAC recommendations for the definition of new
strategic objectives and contingent upon availability
of funds for implementation.
Clinical studies
HNR continues to be a central player inTDR-sponsored clinical trials and is managing
clinical studies that involve 26 countries and 34
principal investigators around the world(Table 5).
Infrastructure and personnel capacity
building
Because study subject requirements are a major
driver of clinical study site selection, HNR is a
central player in TDR-sponsored capacity-building
activities including development of new health
research and health systems infrastructure as well
as personnel capacity. Total investment in 2009 was
US$ 3.2 million. Table 6provides a summary of
these activities.
Financial and human resource analysis
The budget originally assigned to HNR for the
biennium 20082009 was US$ 8.55 million,
revised to US$ 7.86 million in June 2009, and
the amount made available was US$ 6.53 million.
Table 7shows the provisional implementation rates(expenditures) with respect to the latter.
3. Implementation plan20082013 and progress
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Disease Number/type ofstudies
CountriesNumber
ofsubjects
Number ofprincipal
investigators
Number of healthprofessional staff
(total staff)
Onchocerciasis /
LF (loa loa)
1 Phase 2 clinical trial
moxidectin for oncho
(one site)
Ghana 172 1
Democratic Republic
of the Congo 14 (23),
Democratic Republic
of the Congo 16 (28),
Ghana 18 (40),
Liberia 9 (16)
1 Phase 3 clinical trial
of moxidectin for
oncho (three countries,
4 sites)
Democratic Republic
of the Congo, Ghana,
Liberia
172/1500 4
1 clinical field study of
effect of ALB on loa loa(one site)
Cameroon 60 1 3
Schistosomiasis 4 clinical trials Brazil, Mauritania, the
Philippines, United
Republic of Tanzania.
800 4
1 clinical trial Sudan 1
STH
HAT 1 phase III clinical trial Uganda 109 1 (2 sites) 20 (10 per site)
1 phase III clinical trial Uganda 100 1 (2 sites) 20 (10 per site)
Chagas disease 1 clinical trial Argentina, Brazil,Colombia.
3
Leishmaniasis
Dengue 18 18 countries (Argentina,
Bolivia, Brazil, Colombia,
Cuba, Ecuador, El
Salvador, India,
Indonesia, Malaysia,
Mexico, Nicaragua,
Paraguay, the
Philippines, Puerto Rico,
Saudi Arabia, Singapore,Venezuela.)
NA 18 36
Table 5. OVERVIEW OF CLINICAL STUDIES FINANCED AND MANAGED BY HNR IN 2009
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Table 6. OVERVIEW OF CAPACITY BUILDING CONDUCTED BY HNR IN 2009
Table 7. FINANCIAL IMPLEMENTATION 20082009 PROVISIONAL AS OF DATA IN GSM ON 31 DECEMBER 2009
Country(project) Infrastructure building
Personnel capacity building
(project)
Liberia (1 site)
Democratic
Republic of the
Congo (2 sites)
Ghana (1 site)
(Moxidectin
Phase 3)
New research centre built (Liberia, 1 site in Democratic
Republic of the Congo) or buildings unused since the war
renovated to serve as research centre (1 site in Democratic
Republic of the Congo)
Provided to sites in Liberia and Democratic Republic of the Congo:
All clinical, ophthalmological and laboratory equipment
required to conduct Moxidectin Phase 3 study
Oce equipment (4 computers, 1 photocopier, 1 scanner,
1 projector per site)
Two 13 seaters, 0-1 pick-up, 2-10 motorbikes per site
2-3 generators, fuel reserve tanks/site Satellite based internet connection
Provided to OCRC in Ghana: upgrade of laboratory and
ophthalmological equipment, subject accommodation and
transport, satellite based internet connection
Total investment: US$ 2.8 million
GCP training, clinical and ophthalmological
standard operating procedures (SOPs) for all
study team members
GCLP training, laboratory SOPs for all
laboratory staff
Practical training on conduct of GCP
compliant study from Informed Consent
taking via screening, treatment and
treatment follow up through OCRC staff
during observation of conduct of Phase 2
study for key study team members in Liberiaand Democratic Republic of the Congo
Total investment: US$ 0.3 million
Uganda
(Pentamidine
3 days vs 7 days).
1 car provided to both studies (NECT and Pentamidine),
1 generator, 2 microscopes, centrifuge, laptop, printer,
rehabilitation of beds, renovation of ward
Total investment: US$ 70 000
Training of the research team on Good
Clinical Practice
Lab technician trained on HAT diagnosis
Total investment: US$ 4600
18 countries None Dengue clinical training courses (two days each)
Title
JCB approvedbudget
20082009US$ 121 million
A
Fundsavailable
B
Expenditures20082009
C
Implementationas a % of funds
availableD
BL6 Drugs for Helminths/NTDs
8 550 000 6 530 000 5 707 425 87%
New drugs for helminths 6 888 639 4 702 248
Improved use of drugs 1 166 455 507 907
Products for other NTDs 416 205 425 675
Coordination 78 701 71 595
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Disease activein 2009
New drugsR&D
Treatment optimization
Coor-dination
Pharmacology& improved
use of currentdrugs
Pharmaco-epidemiologyin support of
disease control
Markers &
methods for
evaluation of
treatment effects
Onchocerciasis/
LF
4 562 754 77 759 0 1 978
71 595
Schistosomiasis 107 556 0 0 0
STH 0 0 0 35 375
HAT 0 439 736 0 0
Chagas disease 0 14 874 0 0
Leishmaniasis 0 0 0 0
Dengue 0 0 0 395 798
Total 5 707 425
Table 8. EXPENDITURES BY OBJECTIVEDISEASE MATRIX DEFINED BY HNR SAC 2009
PROVISIONAL AS OF DATA IN GSM ON 31 DECEMBER 2009
Table 9. APPROVED BUDGET 20102011
TitleJCB-approved budget 20102011
US$ 121 million
Development and registration of new helminth drugs 6 300 000
Evidence for improved use of currently available drugs 1 010 000
Development of products for other NTDs 390 000
Coordination 160 000
Total BL6 - Drug development and evaluation for helminths
and other neglected tropical diseases
7 860 000
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Table 8shows the breakdown of implementation
(expenditures) in 2008/2009 by strategic objective
and disease according the new SAC-revised
work plan.
Fig. 2compares the planned budget breakdownacross the different strategic objectives of HNRbased on the US$ 7.86 million revised budget to theactivities that could be conducted with the availableUS$ 6.53 million (expenditures + encumbrances).
Funds made available in 20082009 were
US$ 6 530 000 (76% of the US$ 8 550 000approved budget). The figures reported in Tables7and 8are the provisional expenditures (vs. totalobligations of US$ 6 480 408, i.e. 99.2% of theavailable funds) reflected in the data. Moxidectindevelopment accounts for 80% of expenditures.
An additional related project is research forbiomarkers reflecting response of O. volvulustoivermectin. Both of these projects are primarilyfinanced by designated funding obtained from
Wyeth Pharmaceuticals/Pfizer and under thebipartite agreement between TDR and the AfricanProgramme for Onchocerciasis control.
Fig. 3shows the personnel resources available forHNR projects and the fraction of time they spent ondifferent projects by strategic objective and disease.Note that the FTEs available (2.12 G and 2.39P staff FTEs) are lower than the number of staff
assigned to HNR. The reason for one G and two Pstaff not being 100% in HNR is that they are alsoworking on a project assigned to another BL.
HNR human resources are insufficient to ensurethat projects can be advanced as quickly asnecessary and consistent with the originallyestablished timelines for the projects (see section 5,Critical issues and suggested solutions).
Fig. 2. (b) 20082009 obligations (expenditures + encumbrances)
based on available funds (US$ 6.53 million)
Fig. 3. HNR personnel resources available expressed as FTEs
(full time equivalents)
Fig. 2. (a) HNR budget breakdown as planned based
on budget reduction in June 2009 (US$ 7.86 million)
New drugs R&D - moxidectin;$5,600,000
New Drugs R&D - Other;$150,000
Pharmacology & improveduse of current drugs;
$450,000
Coordination;$160,000
Markers & Methodsfor evaluation of
treatment effects;
$1,200,000
Pharmaco-epidemiologyin support of disease control;
$300,000
New drugs R&D - moxidectin;$5,173,326
New Drugs R&D - Other;$119,183
Pharmacology & improveduse of current drugs;
$663,516
Coordination;$71,605
Markers & Methods for evaluationof treatment effects;
$452,781
Pharmaco-epidemiologyin support of disease control; $0
0.00
0.20
0.40
0.60
0.80
1.00
P. Edmonson
E. Chapin
V. Robert
P. OlliaroA. Kuesel
O. Lapujade
A. Kroeger
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3.2 Plan, progress and keymilestones
3.2.1. Overview of new projects
initiated in 2009
In 2009, six new projects and activities were
initiated in line with the redefined strategic focus as
recommended by STAC and the HNR SAC and as
summarized in Table 10.
3.2.2. Progress and milestones bystrategic objective
Objective 1: Development, registration and
field evaluation of new drugs (New drugs for
NTDs)
Development of moxidectin for onchocerciasis and
lymphatic filariasis.
Principal Investigator: Dr Kwablah Awadzi,
Onchocerciasis Chemotherapy Research Centre
(OCRC), Hohoe Hospital, Hohoe, Ghana.
TDR project manager: Dr Annette Kuesel.
Moxidectin (a macrocyclic lactone registeredworldwide (including the United States of America,
USA) for prevention of canine heartworm and
treatment of parasites in cattle, sheep, and horses)
has been developed since 2000 in collaboration
with Wyeth Pharmaceuticals Pharmaceuticals
(now Pfizer). The objective is to see whether
moxidectin has the macrofilaricidal/macrofilaria
sterilizing properties and is a safe enough drug to
be administered through the community directed
mechanism to cure the patient and permanently
interrupt transmission of the disease. Thisdevelopment programme is supported by the
APOC.
Nonclinical study results and clinical data
obtained to date support clinical trials for the oral
administration of moxidectin in subjects 4 years.
Up-to-date complete animal safety data has been
compiled, a suitable tablet formulation has been
developed and 5 clinical pharmacology studies in
healthy volunteers have either been completed or
successfully enrolled in Europe. Phases 2 and 3 are
being conducted in endemic countries. The goal of
Objective / area of HNR focus Projects initiated in 2009
1) New drugs for onchocerciasis, lymphatic
filariasis, soil-transmitted helminthiasis, schis-
tosomiasis, foodborne trematodes and dengue
Identification of potential drug candidates for helminths
2) Treatment optimization & biomarkers Dossiers compiling publicly available data for drugs currently
used for NTDs as a basis for decisions on further activities/
prioritization (e.g. risk-identification and guidance for pharmaco-
epidemiology/vigilance activities)
2a) Pharmacology and improved use of current
drugs
Anthropometric database on patients with visceral leishmaniasis
from different endemic areas
2b) Pharmaco-epidemiology in support of
disease control
Framing of development of methods for pharmaco-epidemi-
ology/vigilance in community directed interventions
2c) Markers and methods of evaluation of
treatment effects
Molecular markers of O. volvulusresponse to ivermectin and tool
for surveillance of ivermectin response by control programmes
Standardization of methods for diagnosis and evaluation of treat-
ment effect in cutaneous leishmaniasis
Table 10. NEW PROJECTS INITIATED BY HNR IN 2009
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this initiative is to obtain a Scientific Opinion from
the European Medicines Agency (EMEA) according
to article 58 and subsequent approval for use by the
endemic countries (targeted for 2013). Deployment
as a validated control tool could occur by 2015.
If results for onchocerciasis are encouraging,development for lymphatic filariasis will be
considered. An overview of the development plan is
presented in section 6.1.
Progress and key achievements (2008)
EMEA scientic advice on preclinical and clinical
development strategy and plan obtained.
Milk excretion study initiated (by Wyeth
Pharmaceuticals).
Phase 2 study enrolment completed (N=172).
Phase 3 study site infrastructure and personnel
capacity building initiated in Liberia and
Democratic Republic of the Congo.
Go decision for initiation of Phase 3 study with 8
mg dose, submission of clinical study protocol to
Ethics Committee (EC) in Liberia and Democratic
Republic of the Congo (08/08), clinical trial
application and import permit request submitted
to Liberia and Democratic Republic of the Congo,
ministries of health (MoH).
Phase 3 study authorization from Liberia (EC,
MoH, Import permit).
Progress and key achievements (2009)
EMEA scientic advice for paediatric study plan
obtained.
Drug interaction and food effect study initi-
ated and completed enrolment (by Wyeth
Pharmaceuticals).
Milk excretion study completed enrolment.
Phase 2 study completed follow up.
Paediatric clinical study protocol approved bythe Special Project Team and submitted to WHO
Ethics Committee (for feedback prior to submis-
sion to Ghana Ethics Committee).
Phase 3 site infrastructure and personnel capacity
building completed.
Phase 3 study initiated in Liberia in April 2009(172 subjects enrolled as of December 2009) and
in Democratic Republic of the Congo in December
2009.
Phase 3 study EC approval obtained in Ghana,
Clinical Trial Application and import permit
request under review by Ghana Food and Drugs
Board.
Project implementation status versus plan
Based on the safety data from the Phase 2 study,
the clinical pharmacology studies in healthy
volunteers conducted by Wyeth Pharmaceuticals
were initiated earlier than originally planned.
Initiation of Phase 3 in Liberia was put back by
9 months due primarily to delays in site capacity
building caused in turn by delays in finalization
of the legal agreement, WHOs implementation
of its new administrative system, delivery of
WHO ordered equipment to the sites (transport,
custom clearance), finalization of documentation
for the ethics committee and regulatory authority
submissions, and longer than anticipated timefor obtaining authorization for study conduct.
Initiation of Phase 3 in the Democratic Republic
of the Congo was further delayed by 8 months
due to logistical challenges and time to receive all
required approvals.
Implications of progress/delays and changes in
the global context for the 20082013 plans
The delay in starting the Phase 3 study jeopardizes
recruitment of the 1500 subjects not treated with
ivermectin for at least 6 months, required as perdiscussions with the EMEA, since implementation
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of ivermectin treatment (CDTI) in the study
areas is expected to occur before all subjects are
recruited. The protocol will have to be amended
and buy-in from the EMEA obtained to allow
recruitment of subjects treated with ivermectin to
reach the total enrolment target and to conduct anadditional safety study. Less than 1500 subjects not
previously treated with ivermectin in the ongoing
study will not affect the ability to draw statistically
valid conclusions regarding the relative efficacy
of moxidectin or ivermectin. This is because the
study size was determined based on the desire to
have 1000 moxidectin-treated subjects for safety
evaluation and this resulted in overpowering from
an efficacy point of view.
Specific activities for 2010
Final analysis of Phase 2 data.
Initiate Phase 3 study in Ghana.
Prepare and submit Phase 3 protocol amendment
to allow enrolment of subjects who are not
ivermectin-nave.
Prepare conduct of and potentially initiate
paediatric study.
Identify sites for community studies, invite
and evaluate proposals, establish contracts
and conduct capacity building for community
studies.
Prepare protocols for community studies
and submit to responsible committees and
authorities.
Leverage
Wyeth Pharmaceuticals investment in
manufacturing site preparation and qualification
(including regulatory inspection), study drug
manufacture and qualification, pre-clinical
toxicology and pharmacology studies, assembly
of regulatory submissions, operational support
for Phase 2 study data management, operational
support of Phase 3 data management,
consultation with European regulatory
authorities (EMEA), regulatory reporting of
drug related Serious Adverse Events (SAEs),
completion of 2 clinical pharmacology studies,conduct of 3 additional clinical pharmacology
studies required for the submission of an
application for a scientific opinion from the
EMEA and drug registration in onchocerciasis
endemic countries.
Wyeth Pharmaceuticals grant of US$ 6 million to
TDR for the conduct of the Phase 3 study.
Other
In October 2009, the takeover of Wyeth
Pharmaceuticals by Pfizer was completed.Discussions between TDR and personnel of
Pfizer in the Emerging Markets unit, to which
moxidectin has been assigned, have been initiated.
As of November 2009, the personnel in the Pfizer
development team are the same as those that
conducted the project withWyeth Pharmaceuticals.
L-praziquantel (L PZQ) for schistosomiasis
Principal Investigator: Dr Matthew H. Todd, Senior
Lecturer, School of Chemistry, the University of
Sydney, Australia.
TDR project manager: Dr Piero L. Olliaro.
This project aims to assess whether synthetic routes
for enantiomer pure L PZQ exist that are chemically
feasible, scalable and economically viable by
identifying and testing routes in the laboratory.
Praziquantel (PZQ) preparations that are available
on the market are racemic 50:50 mixtures of
two stereoisomers. It was shown by the original
developers of the drug that the anthelmintic activity
is concentrated in the laevorotatory ()-isomerwhich has (R)-configuration. This notion was
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repeatedly confirmed by in vitro and in vivo tests.
Most importantly, a randomized double-blind study
on 139 matched pairs of patients infected with S.
japonicumshowed that a single 20 mg/kg dose of
(R)-PZQ was as efficacious as 40 mg/kg of racemic
praziquantel, but (R)-PZQ produced fewer sideeffects than racemic PZQ.
There are several valid reasons for developing an
enantiomer pure PZQ: a decrease in side effects,
closer conformity to guidelines of drug regulatory
agencies, easier administration (currently-used 600
mg PZQ tablets often create swallowing problems).
With WHO/NTD and Medicines for Malaria Venture
(MMV) assistance, we have gathered expertise on
stereosynthesis and identified projects to support
the University of Sydneys approach.
The results of this project will be shared with the
entire community for further refinement and work
via the open source approach.
Progress and key achievements
With the help of WHOs legal department, we
have resolved a series of contractual constraints
and research has now started at the University
of Sydney with substantial support from the
Australian government (Australian Research
Council projects); Research started.
Project implementation status versus plan
On track.
Leverage
TDR contribution was instrumental in leveraging
the Australian Research Council contribution.
Specific activities for 2010
Continue to provide support to open source
project;
Fund specic projects on feasibility.
NEW ACTIVITY: Identification of development
candidates for helminths and dengue.
TDR project manager: Dr Annette Kuesel.
Searches for potential candidates are being
conducted with the support of SAC members andother experts. For potentially eligible candidates,
dossiers are being prepared by external experts
based on publicly available information and,
whenever indicated and possible, proprietary
information from the owner. Three compounds
of interest have been identified and dossiers are
expected to be available by the end of the first
quarter of 2010.
Objective 2: Generation of evidence for
improved use of currently available drugs
(Treatment optimization & Biomarkers)
Objective 2 a) Pharmacology and improved
use of current drugs
Onchocerciasis/lymphatic filariasis
Therapeutic effect of albendazole + DEC in
children with lymphatic filariasis
Principal Investigator: Dr R.K. Shenoy, Filariasis
Chemotherapy Unit, HDS Building, Near
District TB Centre, TD Medical College Hospital
Compound, Alappuzha - 688 011, Kerala, India.
TDR project manager: Dr Janis K. Lazdins-Helds
(new manager: Dr Annette Kuesel).
This project is aimed at defining early pathological
changes in children infected with Brugia malayi and
evaluating whether these are affected by 6-monthly
treatment with diethylcarbamazine and albendazole.
In many tropical countries, the vector-borne
disease lymphatic filariasis (LF) is a major cause
of considerable chronic and acute disability.
Until recently, LF was considered to be a disease
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of adults. Globally, 22 million children under
the age of 15 are estimated to have LF infection,
but little information is available on the clinical
manifestations, particularly of Brugia malayi
infection, in children.
The study titled, A cross sectional study of
children to define the clinical and pathological
changes caused by Brugia malayi infection in an
endemic area, was initiated in 4Q04. Following the
screening of 7 934 children, (3 to 15 years of age),
200 were recruited. All the children enrolled in the
study were followed up every six months over 36
months for occurence of any entry lesions, acute
adenolymphangitis or swelling of the limbs via
routine blood and urine examination, night blood
examination for microfilaria count by Nucleporemembrane filtration, Doppler sonography and
lymphoscintigraphy. At the start of the study and at
each follow-up visit, the children were treated with
single doses of diethyl carbamazine 6 mg/kg and
albendazole 400 mg.
Progress and key achievements
The last child enrolled completed the final follow
up planned in January 2009 and final data became
available in July 2009. Lymphoscintigraphy revealed
lymph-node and lymph-vessel damage in 82% ofthe children at enrolment. In about 67% of the
children this pathology was markedly reduced by
the end of the follow-up period. Microfilaremia and
Bm14 antibody levels had declined.
The results were published (Shenoy et al. 2009)
Project implementation status versus plan
Project as originally planned was completed.
Leverage
A new (non-TDR) study on Effect of Albendazoledose and interval, sponsored by the LF Global
Programme, will be started under a Bill & Melinda
Gates Foundation research grant.
Implications of results
These results show that the drugs used by the
Global Programme to Eliminate Lymphatic Filariasis(GPELF) can reverse subclinical lymphatic damage
in children and that appropriate mass administration
can provide benefits beyond interruption of
transmission in endemic areas. This provides an
important motivation to ensure inclusion of young
children in the mass treatment programmes and a
potent advocacy tool for the GPELF.
Specific activities for 2010
Follow up will continue beyond the originally
planned study end to see whether further reversal of
pathology will occur (pending approval of external
advisors and Ethics Committees).
Budget for 20102011
None required the investigator reported that
sufficient funds for additional follow up are
available from last years budget.
Reduction of loa loa microfilaremia by albendazole
to reduce the risk of ivermectin-induced SAE in loa
loa infected individuals (completed)
Principal Investigator: Dr Joseph Kamgno, Filariasis
Research Centre, Yaound, Cameroon
TDR project manager: Dr Annette Kuesel.
The objective of this project was to evaluate
whether two or six two-monthly treatment
of subjects with loa loa infection reduce the
microfilaremia sufficiently to reduce the risk of
severe and/or serious adverse reactions to treatment
with ivermectin, for onchocerciasis or lymphaticfilariasis control.
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Loiasis is a parasitic infection endemic in the rain
forest areas in sub-Saharan Africa caused by the filarial
nematode loa loa. People heavily infected with loa loa
who take ivermectin can have severe and/or serious
adverse events , including encephalopathy and death.Implementation of Community Directed Treatment
with Ivermectin (CDTI) in onchocerciasis-loa loa
co-endemic areas can progress only very slowly since
appropriate medical care has to be made available in
case of such SAEs. The fear of serious and/or severe
adverse events leads to a reduced participation of
the population in CDTI. Following an analysis of
SAEs during onchocerciasis control and a risk-benefit
assessment, it was decided not to move albendazole-
ivermectin mass treatment into areas that are
co-endemic for lymphatic filariasis and loiasis.
Progress and key achievements
The study was completed in 2009. The results show
that neither treatment regimen examined reduces
loa loa microfilaremia to the extent required to
substantially reduce the risk of severe or serious
adverse events upon mass-treatment with ivermectin
for onchocerciasis or LF control in loa loa co-endemic
areas. Thus, this study will not have the anticipated
outcome (accelerated expansion of the use of
ivermectin against onchocerciasis and implementation
of ivermectin + albendazole treatment in lymphatic
filariasis loiasis co-endemic zones).
Leverage
GSK, The World Bank, and APOC provided
designated funds to TDR for the study. The study
drug was donated by GSK.
Schistosomiasis
Evaluation of praziquantel combination with
oxamniquine for schistosomiasis
Principal investigator: Professor Mamoun Homeida,
Academy of Medical Sciences and Technology,Khartoum, Sudan.
TDR project manager: Mr Olivier Lapujade.
This is a study designed to evaluate the
pharmacokinetics efficacy and safety of using
both drugs in combination with the purpose of
enhancing not only efficacy but also to protect
praziquantel from resistance, especially in view of
the dramatic expansion of its use.
The study has been on hold for more than a year
due to difficulties in accessing oxamniquine (theonly source is in Brazil).
Effective and safe dose (40 versus 60 mg/kg) of
praziquantel for treatment of schistosomiasis
Principal Investigators: Dr Otvio Pieri, Laboratory
of Eco-epidemiology & Control of Schistosomiasis
& Soil-transmitted Helmi