Drug Development and Evaluation PDF

ANNUAL REPORT 2009
TDR BUSINESS LINE 6

Drug development and evaluation
for helminths and other
neglected tropical diseases
DRUG R&D FOR HELMINTHS AND OTHER NEGLECTED TROPICAL DISEASES
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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 Congo
Printed by the WHO Document Production Services, Geneva, Switzerland
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Table of contents
List of tables
Table 1. Denition 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 nanced 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 dened 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 ...................................................................................... 25
Table 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 .............................................................................................................................. 7
Collaborations 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 ......................... 40
4.1 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 for
Onchocerciasis Control
APW Agreement for Performance of Work
BENEFIT Benznidazole Evaluation For
Interrupting Trypanosomiasis
BL6 (HNR) Drug Development and Evaluation for
Neglected Tropical Diseases
CD Chagas disease
CDI Community directed interventions
CDTI Community directed treatment with
ivermectin
CIR Community based interventions
CL Cutaneous leishmaniasis
DEC Diethylcarbamazine
DENCO Dengue control clinical study
DNDi Drugs for Neglected Diseases
initiative
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 Eliminate
Lymphatic Filariasis
HAT Human African trypanosomiasis
HNR Drug Development and Evaluation for
Neglected Tropical Diseases (BL6)
IV Intravenous
IVM Ivermectin
LF Lymphatic lariasis
MDA Mass drug administration
MMV Medicines for Malaria Venture
MoH Ministry of Health
MPR Anti-Malarial Policy & Access
NTD Neglected tropical disease
OCRC Onchocerciasis Chemotherapy
Research Centre
O.v. Onchocerca volvulus
OXQ Oxamniquine
PCR Polymerase chain reaction
PZQ Praziquantel
R&D Research and development
SAC Strategic and Scientic Advisory
Committee
SAE Serious adverse events
SoP Standard operating procedure
SPT Special Project Team advisory
committee for projects requiring
special expertise and/or more intense
ongoing involvement of external
experts than can be provided by the
SAC (SPTs are in place for moxidectin
development, ivermectin response
markers research and Chagas disease
projects)
STAC Scientic and Technical Advisory
Committee
STH Soil transmitted helminths
TCC Technical Consultative Committee
TDR Special Programme for Research and
Training 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 Denitions
Working Group 1998).
Development Studies on the pharmacokinetics, safety and ecacy of a drug or drug combinations in humans aimed at
determining whether the drug or drug combination studied has the clinical target product prole 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 rst 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 ecacious in disease animal model with no overt toxicity and with characteristics potentially
suitable for cost-eective scale-up.
Lead optimized Optimized lead compound with in vitro and in vivo activity, pharmacokinetic and toxicity prole potenti-
ally consistent with target product prole, and amenable to cost-eective scale-up of manufacturing can
be evaluated for development track decision.
Pharmaco-
epidemiology
The study of the use and eects 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 benets 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
eects or any other drug related problems Specic 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 benet, harm, eectiveness and risk of medicines;
encouraging their safe, rational and more eective (including cost-eective) use; and
promote understanding, education and clinical training in pharmacovigilance and its eective
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 scientic 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 rst study
in humans.
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Risk management Iterative process of (1) assessing a products benet-risk balance, (2) developing and implementing tools
to minimize its risks while preserving its benets, (3) evaluating tool eectiveness and reassessing the
benet-risk balance, and (4) making adjustments, as appropriate, to the risk minimization tools to further
improve the benet-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 specications, 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 denition 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 dierent units within
TDR which is expected to yield a better result or a more eciently obtained result than if each unit was
pursuing the work separately.
Target product
profle
Summary of pharmaceutical, ecacy 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 Intensied Disease Management
for diseases for which cost-effective control
interventions do not exist for wide-scale use (the
so-called tool-decient 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 insufcient
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
denition of the strategic objectives of HNR (drug
development and evaluation for neglected tropical
disease BL6):
(1) Development, registration and eld 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
Scientic and Technical Advisory Committee
(STAC) in 2009, (see section 6.4), the scope and
portfolio of activities for the coming years were
redened by the HNR Strategic and Scientic
Advisory Committee (SAC) with input from the
WHO/Neglected Tropical Diseases department and
other key partners to cover two specic objectives:
1. Development, registration and eld evaluation of
new drugs for NTDs including identication of
suitable 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 nal data of three studies became available in
2009:
Initial lymph node and vessel pathology
can be reversed if lymphatic lariasis (LF) is
treated in childhood with a combination of
diethylcarbamazine plus albendazole. The
rst-ever study in children with parasitological
or immunological signs of Brugia malayi infection
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conducted in India shows that mass drug
administration not only affects transmission,
but also has the potential to have effects on
development 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 lariasis. 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 efcacy
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 classication 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 revised
classication 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 for
NTDs
Onchocerciasis and lymphatic lariasis
Moxidectin development Phase 2 completed,
Phase 3 started. Ivermectin does not sterilize or
kill the adult O. volvulus. Transmission could be
interrupted with a macrolaricidal or macrolaria
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 (Pzer
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-treatment
follow-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 lariasis
Markers for evaluation of effect of ivermectin in
Onchocerca volvulus a north-south collaborative
project 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 ve invited
proposals were received and are undergoing review
by the responsible Special Project Team.
Pharmacology and improved use of current
drugs for lymphatic lariasis trial shows clinical
benets of treating children. The rst-ever study
in children with parasitological or immunological
signs of Brugia malayi infection 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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TDR BL6 2009 Report
that administration of the drugs used by the Global
Programme to Eliminate Lymphatic Filariasis
can provide benets beyond the interruption of
transmission (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
microlariae. 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 microlarial loads completed follow up
in 2009. The results show that neither regimen
can reduce loa loa microlaraemia 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
efcacy 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
rst 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
difcult. In 2009 WHO/NTD and TDR/HNR
hosted a workshop of experts which developed a
standardized protocol for CL.
Human African trypanosomiasis (HAT)
Improved use of eornithine in stage 2 human
African trypanosomiasis (HAT) study completed
and analysis under way. Treatment for stage 2 HAT
by intravenous infusion of eornithine 4 times a day
(each infusion taking 2 hours) is cumbersome and
difcult, particularly in remote areas. The NECT
(Nifurtimox-Eornithine Combination Therapy)
phase 3 study in Uganda was conducted to evaluate
an alternative treatment that would be as effective
as standard eornithine 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 (led 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 eld conditions; the drug
pharmacokinetics support a shorter treatment. The
ongoing study is comparing the safety and efcacy
of a three-day pentamidine regimen against the
standard seven-day regimen. In 2009, intensive
consultations with the WHO control programme
(NTD) and DNDi conrmed 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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TDR BL6 2009 Report
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complete recruitment by the end of 2010. Due to
nancial constraints and major investments in other
HAT-related programmes DNDi is unable to take
part 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 classication of dengue
new classication adopted by countries and
undergoing validation. In 2009, validation of
the new evidence-based classication of dengue
disease into three levels of severity was initiated
in 18 countries. Interim results show that dengue
physicians appreciate the new classication because
of user-friendliness, decision support for clinical
management and triage particularly during disease
outbreaks. Three countries adopted the revised
classication 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 of
Neglected Tropical Diseases (WHO/NTD), along
with the HNRs SAC, contributed to dening
the priority research agenda and identifying
specic research projects. HNR also has a long-
standing collaboration under a Memorandum of
Understanding with APOC.
HNR works with regional and country ofces, as
well as in a project specic manner with researchers
in developing and developed countries, non-prot
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 ofce staff.
Inuencing 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 nal declaration of the G8
summit 2009 and various initiatives of the Italian
presidency to raise the prole of NTDs.
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TDR BL6 2009 Report
1.1 Context
The current WHO approach to control NTDs is
based on two different strategies.
1. For diseases for which tools are not available or
difcult to use (tool-decient diseases such
as Buruli ulcer, Chagas disease, human African
trypanosomiasis and leishmaniasis outside the
Indian subcontinent), the strategy focuses on
increasing disease awareness, early case detection
and making the current drugs available at an afford-
able price (innovative, intensied treatment).
2. For diseases for which there are safe and effective
drugs (tool-ready diseases such as cysticercosis,
dracunculiasis, foodborne trematode
infections, lymphatic lariasis, onchocerciasis,
schistosomiasis and soil-transmitted
helminthiasis), the strategy is to administer these
drugs widely to populations at risk (preventive
chemotherapy) for transmission control.
When different diseases coexist in the same
area, drugs are co-administered (prophylactic
chemotherapy).
For the rst group of diseases, there is an urgent
need to develop safe and affordable new drugs.
For the second group of diseases, drug doses
and regimens need to be optimized - which
requires additional data on pharmacokinetics,
pharmacodynamics, drug interactions, and new
formulations. Control of these diseases currently
depends on a single drug (e.g. praziquantel for
schistosomiasis, ivermectin for onchocerciasis)
which makes them vulnerable to the emergence of
parasite resistance. Therefore, new drugs and drug
combinations are needed for this group of diseases
as well.
1. Context, strategic objectives
and framework
Innovation/
pharmaceutical
gap
Basic
science
Product
discovery
Product
development
(R&D)
Product use
Schools,
communities
Health
systems
Operational
research
Tool ready
Lymphatic flariasis, Leprosy, Onchocerciasis,
Schistosomiasis, Helminthiasis, Trachoma, Yaws,
(visceral leishmaniasis Indian subcontinent)
Tool decient
Human African trypanosomiasis, Chagas dis.
Buruli ulcer, Leishmaniasis, Dengue
Vulnerable diseases
Lymphatic flariasis, Onchocerciasis,
Schistosomiasis, (Helminthiases)
Fig. 1. Context of HNR objectives
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TDR BL6 2009 Report
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For both groups of diseases, methods and systems
to monitor efcacy, 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 dened in the 20082013 Business
Plan are:
1. Development and registration of new drugs
for onchocerciasis, lymphatic lariasis,
schistosomiasis and other helminthiasis and eld
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 (efcacy and safety), including drug
combinations;
Assessing the efcacy and safety proles of
drugs co-administered in mass distribution
programmes for different diseases;
Evaluating product safety and efcacy 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 redene 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 redene HNR mission and
objectives with the end-product being a document
including a situation analysis, identifying research
needs in support of control and dening how HNR
should 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 the
mandates of other relevant partners.
This situation analysis was completed in 2009,
and will lead to the completion in 2010 of a
modied business plan taking into account both
the priorities/areas of focus as per HNR SAC advice
and TDR and HNR nancial 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 2 and 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 lariasis, 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 by
dedicated organizations).
Activities include identication of drug
development candidates, transitioning from
pre-development into development, registration
and validation for use in the eld, 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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13
TDR BL6 2009 Report
HNRs work requires the building and strengthening
of local capacities and close interaction with disease
control programmes, health systems and regulatory
authorities in developing countries.
The efciency 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 currently
available drugs for NTDs (for
short: Treatment optimization &
Biomarkers)
This activity supports the control strategies,
including both integrated, intensied 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 currently
available drugs: The dosing regimens used for
treating many of the NTDs are often based on
incomplete pharmacological, efcacy 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 be
combined with other drugs for improved efcacy
(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 (efcacy, safety, effectiveness, resistance)
of interventions when used in real life. These
data are essential to optimize the impact of
interventions. However, methods (including
pharmacovigilance) to collect and analyse the
relevant data are imperfect and not adapted to
the 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 benet
will be improved case management with less
cumbersome 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 and
providing 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 sufcient
exibility to address unanticipated control
programme issues.
Table 4 presents 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 completing
enrolment as soon as possible.
14
TDR BL6 2009 Report
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Table 2. HNR PORTFOLIO COMPOSITION IN 2009 BY DISEASE AND STRATEGIC OBJECTIVES
Disease
active in 2009
New drugs
for NTDs
Treatment optimization and biomarkers
Pharmacology
& improved use
of current drugs
Pharmaco-epidemiology
in support of
disease control
Markers & methods
for evaluation of
treatment eects
Onchocerciasis/
LF
Moxidectin for Oncho
(Phase 3)
Drug develop-
ment candidate
identication
Efect of ALB on loa loa
microlaremia
Efect 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
identication
PZQ-OXQ combination
Praziquantel dose
comparison
Systematic reviews
(urinary & intestinal)
Dossiers on drugs in
use
STH Drug develop-
ment candidate
identication
use
HAT Nifurtimox + eforni-
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
identication
Validation of new
disease classication
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TDR BL6 2009 Report
Table 3. HNR PORTFOLIO PLANNED FOR 2010 BY DISEASE AND STRATEGIC OBJECTIVES
Disease
active in 2009
New drugs
for NTDs
Pharmacology
& improved use
of current drugs
in support of
disease control
Markers & methods
for evaluation of
treatment eects
Onchocerciasis/
LF
Moxidectin for Oncho
(Phase 3)
Drug develop-
ment candidate
identication
Efect 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
identication
PZQ-OXQ combination
Systematic reviews
(urinary & intestinal)
use
STH Drug develop-
ment candidate
identication
Dossiers on drugs in use
Improved benzimidazoles
HAT Nifurtimox+efornithine
(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 eect
Leishmaniasis Standardization of
methods for Dx and
TxFU of cutaneous
leishmaniasis
Biomarkers of treat-
ment eect
Dengue Drug develop-
ment candidate
identication
Validation of new
disease classication
16
TDR BL6 2009 Report
BL6
BL strategic objectives Disease Project End products Expected outcomes
1. New drugs for onchocerciasis, LF, STH,
schistosomiasis, foodborne trematodes
and dengue
Onchocerciasis/LF Moxidectin for onchocerciasis (and

lymphatic lariasis)
(i) Clinical data from Phase 2 and 3 trials to assess
whether moxidectin meets target product prole for
registration (2011)
(ii) community study data on eect on onchocerciasis
transmission and safety during mass treatment (2015)
(i) Filing by manufacturer for registration
(ii) EMEA scientic 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
Schistosomiasis L-praziquantel for schistosomiasis Data to assess whether enantiopure L-praziquantel meets
target product prole for registration (2015)
(i) Filing by manufacturer for registration and/or list of essen-
tial drugs; (ii) registration/adoption by concerned endemic
countries.
Helminths, dengue Drug development candidates for helminths
and dengue
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)
2. Generation of evidence for improved
use of currently available drugs (treat-
ment optimization and biomarkers)
All Dossiers on drugs currently used for NTDs (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 agging to disease
control programmes, design of studies to test and optimize
pharmaco-epidemiology/vigilance for NTDs, identication/
prioritization of HNR research (20102013)
Identication of research questions for treatment optimiza-
tion studies. Risk management plans established by WHO
disease control programmes and/or national disease control
programmes
2a. Pharmacology and improved use of
current drugs
LF Therapeutic efect of albendazole +
diethylcarbamazine (DEC) in children with
lymphatic lariasis
Clinical evidence of the safety and ecacy in curing and
reversing lymphatic lesions in children infected with
Brugia malayi (20092012)
Lymphatic lariasis control programmes include cure of
infection and regression of early lymphatic lesions in children
(currently aiming only at interruption of transmission)
Onchocerciasis / LF Ecacy of albendazole in reducing loa loa
microlaremia
Proof of concept of ecacy of albendazole against loa loa
(2009)
Accelerated expansion of IMV use against onchocerciasis,
implementation of IV + ALB treatment in LF-loiasis co-
endemic areas
Schistosomiasis

Combination of praziquantel and oxam-
niquine for schistosomiasis
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
Efective and safe dose of PZQ for Tx of
schistosomiasis
Data to assess the safety and ecacy 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
Systematic reviews in urinary and intestinal
schistosomiasis
Evidence base for research and treatment policy recom-
mendations for schistosomiasis (2010)
Use of results to inform research priority setting and treat-
ment recommendations
Leishmaniasis Anthropometric database on patients with
visceral leishmaniasis from dierent endemic
areas
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)
Chagas disease Benznidazole for the treatment of patients
in the late indeterminate or early chronic
phase of T. cruzi infection (BENEFIT)
Safety and ecacy (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. cruzi infected individuals after Tx with benznidazole.
Change of treatment guidelines.
Table 4. HNR PROJECTS, END PRODUCTS AND EXPECTED OUTCOMES
Projects initiated/planned in 2009 are indicated in italics
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TDR BL6 2009 Report
1. New drugs for onchocerciasis, LF, STH,
schistosomiasis, foodborne trematodes
and dengue
Onchocerciasis/LF Moxidectin for onchocerciasis (and

lymphatic lariasis)
(i) Clinical data from Phase 2 and 3 trials to assess
whether moxidectin meets target product prole for
registration (2011)
(ii) community study data on eect on onchocerciasis
transmission and safety during mass treatment (2015)
(i) Filing by manufacturer for registration
(ii) EMEA scientic 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
Schistosomiasis L-praziquantel for schistosomiasis Data to assess whether enantiopure L-praziquantel meets
target product prole for registration (2015)
(i) Filing by manufacturer for registration and/or list of essen-
tial drugs; (ii) registration/adoption by concerned endemic
countries.
Helminths, dengue Drug development candidates for helminths
and dengue
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)
2. Generation of evidence for improved
use of currently available drugs (treat-
ment optimization and biomarkers)
All Dossiers on drugs currently used for NTDs (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 agging to disease
control programmes, design of studies to test and optimize
pharmaco-epidemiology/vigilance for NTDs, identication/
prioritization of HNR research (20102013)
Identication of research questions for treatment optimiza-
tion studies. Risk management plans established by WHO
disease control programmes and/or national disease control
programmes
current drugs
LF Therapeutic efect of albendazole +
lymphatic lariasis
Clinical evidence of the safety and ecacy in curing and
reversing lymphatic lesions in children infected with
Brugia malayi (20092012)
Lymphatic lariasis control programmes include cure of
infection and regression of early lymphatic lesions in children
(currently aiming only at interruption of transmission)
Onchocerciasis / LF Ecacy of albendazole in reducing loa loa
microlaremia
Proof of concept of ecacy of albendazole against loa loa
(2009)
Accelerated expansion of IMV use against onchocerciasis,
implementation of IV + ALB treatment in LF-loiasis co-
endemic areas
Schistosomiasis

Combination of praziquantel and oxam-
niquine for schistosomiasis
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
Efective and safe dose of PZQ for Tx of
schistosomiasis
Data to assess the safety and ecacy 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
schistosomiasis
Evidence base for research and treatment policy recom-
mendations for schistosomiasis (2010)
Use of results to inform research priority setting and treat-
ment recommendations
Leishmaniasis Anthropometric database on patients with
visceral leishmaniasis from dierent endemic
areas
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)
Chagas disease Benznidazole for the treatment of patients
in the late indeterminate or early chronic
phase of T. cruzi infection (BENEFIT)
Safety and ecacy (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. cruzi infected individuals after Tx with benznidazole.
Change of treatment guidelines.
18
TDR BL6 2009 Report
BL6
current drugs (Type F)
Human African
trypanosomiasis

Nifurtimox and eornithine regimen
(NECT) for the treatment of 2nd stage HAT
Data validating a 10-day regimen as providing ecacy
equivalent to that of the standard 14-day eornithine
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
Three-day pentamidine treatment regimen
for 1st stage HAT
Data validating the ecacy 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
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
New method(s) to collect safety, ecacy and resistance data
adapted to the conditions of use for community directed
intervention in countries where health systems are insuf-
ciently developed
Provide control programmes with additional data to dene
a surveillance plan and with methods to implement for
monitoring drug safety, ecacy and resistance. Contribute to a
better knowledge of drug eects (adverse events, ecacy and
resistance) and then a better use of the drug.
2c. Markers and methods of evaluation
of treatment efects
Onchocerciasis

Molecular markers of O. volvulus response
to ivermectin and tool for surveillance of
ivermectin response by control programmes
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
Transdermal delivery of diethylcarbam-
azine-citrate (DEC patch) as a diagnostic
tool for onchocerciasis
Data from clinical and eld studies showing that the DEC
patch can diagnose O. volvulus infection, is safe and suf-
ciently specic (2008). Legal agreement between WHO
and 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 treatment
in areas with long-term onchocerciasis control and
surveillance post treatment discontinuation
Availability of DEC patch to control programmes at cost
Chagas disease Standardized PCR for diagnosing Chagas
disease in the clinic
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
Dengue Revised dengue classication and updated
case management guide
Clinical evidence to validate an improved dengue clas-
sication and case management guide (2010)
Adoption of a new dengue classication for better patient
identication and case management
Leishmaniasis Standardization of methods for diagnosis
and evaluation of treatment eect
A surrogate marker of treatment ecacy to reduce time for
initial determination of cure
Improved case management; reduced clinical trial time and
possibly R&D time
Projects initiated/planned in 2009 are indicated in italics
See also Section 6.6
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TDR BL6 2009 Report
current drugs (Type F)
Human African
trypanosomiasis

Nifurtimox and eornithine regimen
(NECT) for the treatment of 2nd stage HAT
Data validating a 10-day regimen as providing ecacy
equivalent to that of the standard 14-day eornithine
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
Three-day pentamidine treatment regimen
for 1st stage HAT
Data validating the ecacy 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
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
New method(s) to collect safety, ecacy and resistance data
adapted to the conditions of use for community directed
intervention in countries where health systems are insuf-
ciently developed
Provide control programmes with additional data to dene
a surveillance plan and with methods to implement for
monitoring drug safety, ecacy and resistance. Contribute to a
better knowledge of drug eects (adverse events, ecacy and
resistance) and then a better use of the drug.
2c. Markers and methods of evaluation
of treatment efects
Onchocerciasis

Molecular markers of O. volvulus response
to ivermectin and tool for surveillance of
ivermectin response by control programmes
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
Transdermal delivery of diethylcarbam-
azine-citrate (DEC patch) as a diagnostic
tool for onchocerciasis
Data from clinical and eld studies showing that the DEC
patch can diagnose O. volvulus infection, is safe and suf-
ciently specic (2008). Legal agreement between WHO
and 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 treatment
in areas with long-term onchocerciasis control and
surveillance post treatment discontinuation
Availability of DEC patch to control programmes at cost
Chagas disease Standardized PCR for diagnosing Chagas
disease in the clinic
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
Dengue Revised dengue classication and updated
case management guide
Clinical evidence to validate an improved dengue clas-
sication and case management guide (2010)
Adoption of a new dengue classication for better patient
identication and case management
Leishmaniasis Standardization of methods for diagnosis
and evaluation of treatment eect
A surrogate marker of treatment ecacy to reduce time for
initial determination of cure
Improved case management; reduced clinical trial time and
possibly R&D time
20
TDR BL6 2009 Report
BL6
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-prot
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
lariasis. 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-prot 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 optimize
implementation 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
nancial 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, sano-aventis, the
Wellcome Trust, The World Bank, and Wyeth
Pharmaceuticals (now Pzer) contributed cash or
in-kind support.
BL6
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TDR BL6 2009 Report
3.1 Scope of activities
in 20082009
Overview of portfolio
An overview of the portfolio has been provided
in the context of the strategic framework where
Table 2 shows an overview of HNR activities in
2009 by strategic objective and disease in the matrix
dened with the HNR SAC and Table 3 shows the
scope of activities planned for 2010 in line with
STAC recommendations for the denition of new
strategic objectives and contingent upon availability
of funds for implementation.
Clinical studies
HNR continues to be a central player in
TDR-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 6 provides 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 7 shows the provisional implementation rates
(expenditures) with respect to the latter.
3. Implementation plan
20082013 and progress
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TDR BL6 2009 Report
BL6
Disease
Number/type of
studies
Countries
Number
of
subjects
Number of
principal
investigators
Number of health
professional sta
(total sta)
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 eld study of
eect 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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TDR BL6 2009 Report
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
Ofce 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 sta
Practical training on conduct of GCP
compliant study from Informed Consent
taking via screening, treatment and
treatment follow up through OCRC sta
during observation of conduct of Phase 2
study for key study team members in Liberia
and 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 approved
budget
20082009
US$ 121 million
A
Funds
available
B
Expenditures
20082009
C
Implementation
as a % of funds
available
D
BL6 Drugs for Helminths/
NTDs
8550000 6530000 5707425 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
24
TDR BL6 2009 Report
BL6
Disease active
in 2009
New drugs
R&D
Treatment optimization
Coor-
dination
Pharmacology
& improved
use of current
drugs
Pharmaco-
epidemiology
in support of
disease control
Markers &
methods for
evaluation of
treatment eects
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 OBJECTIVE-DISEASE MATRIX DEFINED BY HNR SAC 2009
(PROVISIONAL AS OF DATA IN GSM ON 31 DECEMBER 2009)
Table 9. APPROVED BUDGET 2010-2011
Title
JCB-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
BL6
25
TDR BL6 2009 Report
Table 8 shows the breakdown of implementation
(expenditures) in 2008/2009 by strategic objective
and disease according the new SAC-revised
work plan.
Fig. 2 compares the planned budget breakdown
across the different strategic objectives of HNR
based on the US$ 7.86 million revised budget to the
activities that could be conducted with the available
US$ 6.53 million (expenditures + encumbrances).
Funds made available in 20082009 were
US$ 6 530 000 (76% of the US$ 8 550 000
approved budget). The gures reported in Tables
7 and 8 are the provisional expenditures (vs. total
obligations of US$ 6 480 408, i.e. 99.2% of the
available funds) reected in the data. Moxidectin
development accounts for 80% of expenditures.
An additional related project is research for
biomarkers reecting response of O. volvulus to
ivermectin. Both of these projects are primarily
nanced by designated funding obtained from
Wyeth Pharmaceuticals/Pzer and under the
bipartite agreement between TDR and the African
Programme for Onchocerciasis control.
Fig. 3 shows the personnel resources available for
HNR projects and the fraction of time they spent on
different projects by strategic objective and disease.
Note that the FTEs available (2.12 G and 2.39
P staff FTEs) are lower than the number of staff
assigned to HNR. The reason for one G and two P
staff not being 100% in HNR is that they are also
working on a project assigned to another BL.
HNR human resources are insufcient to ensure
that projects can be advanced as quickly as
necessary and consistent with the originally
established 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 & improved
use of current drugs;
$450,000
Coordination;
$160,000
Markers & Methods
for evaluation of
treatment eects;
$1,200,000
in support of disease control;
$300,000
New drugs R&D - moxidectin;
$5,173,326
New Drugs R&D - Other;
$119,183
Pharmacology & improved
use of current drugs;
$663,516
Coordination;
$71,605
Markers & Methods for evaluation
of treatment eects;
$452,781
in support of disease control; $0
0.00
0.20
0.40
0.60
0.80
1.00
P. Edmonson
E. Chapin
V. Robert
P. Olliaro A. Kuesel
O. Lapujade
A. Kroeger
26
TDR BL6 2009 Report
BL6
3.2 Plan, progress and key
milestones
3.2.1. Overview of new projects
initiated in 2009
In 2009, six new projects and activities were
initiated in line with the redened strategic focus as
recommended by STAC and the HNR SAC and as
summarized in Table 10.
3.2.2. Progress and milestones by
strategic objective
Objective 1: Development, registration and
eld evaluation of new drugs (New drugs for
NTDs)
Development of moxidectin for onchocerciasis and
lymphatic lariasis.
Principal Investigator: Dr Kwablah Awadzi,
Onchocerciasis Chemotherapy Research Centre
(OCRC), Hohoe Hospital, Hohoe, Ghana.
TDR project manager: Dr Annette Kuesel.
Moxidectin (a macrocyclic lactone registered
worldwide (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 Pzer). The objective is to see whether
moxidectin has the macrolaricidal/macrolaria
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. This
development 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
lariasis, soil-transmitted helminthiasis, schis-
tosomiasis, foodborne trematodes and dengue
Identication 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-identication and guidance for pharmaco-
epidemiology/vigilance activities)
2a) Pharmacology and improved use of current
drugs
Anthropometric database on patients with visceral leishmaniasis
from dierent 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 eects
Molecular markers of O. volvulus response to ivermectin and tool
for surveillance of ivermectin response by control programmes
Standardization of methods for diagnosis and evaluation of treat-
ment eect in cutaneous leishmaniasis
Table 10. NEW PROJECTS INITIATED BY HNR IN 2009
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27
TDR BL6 2009 Report
this initiative is to obtain a Scientic 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 lariasis will be
considered. An overview of the development plan is
presented in section 6.1.
Progress and key achievements (2008)
EMEA scientifc 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 scientifc 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 by
the 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 nalization
of the legal agreement, WHOs implementation
of its new administrative system, delivery of
WHO ordered equipment to the sites (transport,
custom clearance), nalization of documentation
for the ethics committee and regulatory authority
submissions, and longer than anticipated time
for 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 per
discussions with the EMEA, since implementation
28
TDR BL6 2009 Report
BL6
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 an
additional 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 efcacy
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 efcacy point of view.
Specic 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 qualication
(including regulatory inspection), study drug
manufacture and qualication, 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 scientic 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 Pzer was completed.
Discussions between TDR and personnel of
Pzer in the Emerging Markets unit, to which
moxidectin has been assigned, have been initiated.
As of November 2009, the personnel in the Pzer
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 ()-isomer
which has (R)-conguration. This notion was
BL6
29
TDR BL6 2009 Report
repeatedly conrmed by in vitro and in vivo tests.
Most importantly, a randomized double-blind study
on 139 matched pairs of patients infected with S.
japonicum showed that a single 20 mg/kg dose of
(R)-PZQ was as efcacious as 40 mg/kg of racemic
praziquantel, but (R)-PZQ produced fewer side
effects 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 identied projects to support
the University of Sydneys approach.
The results of this project will be shared with the
entire community for further renement 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.
On track.
Leverage
TDR contribution was instrumental in leveraging
the Australian Research Council contribution.
Continue to provide support to open source
project;
Fund specifc projects on feasibility.
NEW ACTIVITY: Identication of development
candidates for helminths and dengue.
Searches for potential candidates are being
conducted with the support of SAC members and
other 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 identied and dossiers are
expected to be available by the end of the rst
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 lariasis
Therapeutic effect of albendazole + DEC in
children with lymphatic lariasis
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 dening 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 lariasis (LF) is a major cause
of considerable chronic and acute disability.
Until recently, LF was considered to be a disease
30
TDR BL6 2009 Report
BL6
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 dene 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 microlaria count by Nuclepore
membrane ltration, 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.
The last child enrolled completed the nal follow
up planned in January 2009 and nal data became
available in July 2009. Lymphoscintigraphy revealed
lymph-node and lymph-vessel damage in 82% of
the children at enrolment. In about 67% of the
children this pathology was markedly reduced by
the end of the follow-up period. Microlaremia and
Bm14 antibody levels had declined.
The results were published (Shenoy et al. 2009)
Project as originally planned was completed.
Leverage
A new (non-TDR) study on Effect of Albendazole
dose 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 benets 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.
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
sufcient funds for additional follow up are
available from last years budget.
Reduction of loa loa microlaremia 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
The objective of this project was to evaluate
whether two or six two-monthly treatment
of subjects with loa loa infection reduce the
microlaremia sufciently to reduce the risk of
severe and/or serious adverse reactions to treatment
with ivermectin, for onchocerciasis or lymphatic
lariasis control.
BL6
31
TDR BL6 2009 Report
Loiasis is a parasitic infection endemic in the rain
forest areas in sub-Saharan Africa caused by the larial
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-benet
assessment, it was decided not to move albendazole-
ivermectin mass treatment into areas that are
co-endemic for lymphatic lariasis and loiasis.
The study was completed in 2009. The results show
that neither treatment regimen examined reduces
loa loa microlaremia 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
lariasis 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 efcacy and safety of using
both drugs in combination with the purpose of
enhancing not only efcacy 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 difculties in accessing oxamniquine (the
only 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 Helminthiasis, Oswaldo Cruz
Foundation - FIOCRUZ, Rio de Janeiro, Brazil;
Dr Vicente Belizario, National Institutes of Health,
University of the Philippines; Manila, Philippines;
Dr Mohamed Ouldabdallahi dit Hamad, Institut
National de Recherches en Sant Publique a,
Nouakchott, Mauritania; Dr Lwambo Nicholas
Joseph Stephen, National Institute for Medical
Research, Mwanza Medical Research Centre,
Mwanza, United Republic of Tanzania.
TDR project manager: Dr Piero L. Olliaro
The dose-effect relationship is not well established
for praziquantel; currently both 40 and 60 mg/kg
are recommended and registered for the treatment
of schistosomiasis (independently of the type).
However, they have never been compared formally
32
TDR BL6 2009 Report
BL6
in randomized controlled trials. With the expansion
of the use of praziquantel (chemo prophylactic
treatment of at-risk populations), policy decision-
makers are requesting information on which dose
should be used in their respective settings.
To address this question, TDR has supported a
multi-country study (800 patients) comparing these
two doses in children with intestinal schistosomiasis
in Brazil, Mauritania, and the United Republic
of Tanzania where S. mansoni is endemic, and
in the Philippines, (S. japonicum). The study
has been completed and data from the different
centres analysed.
The study shows that PZQ at both 40 and 60mg/
kg is highly effective (>90%) in treating intestinal
schistosomiasis in school-aged children at all
locations except the United Republic of Tanzania
(~80%, due to high pre-treatment parasite loads).
Results support current WHO recommendations
and show no need for increased dose. The
Philippines has already changed its national policy
based on this study; WHO/NTD will coordinate
policy uptake for the other countries.
Both the study conduct and analysis, and policy
follow-up are done in close collaboration with
WHO/NTD.
All studies completed;
Database centralized and cleaned;
Analyses of individual studies completed;
Individual patient data meta-analysis completed;
Investigators meeting held to fnalise analyses
and interpretation of results;
Results support current WHO recommendation
to use PZQ at 40mg/kg;
Interaction with WHO/NTD and control
programmes for policy uptake.
Study conduct and analysis completed;
Policy uptake to continue in 2010.
Leverage
Country programmes and WHO/NTD contribute
resources and expertise.
Publish results;
Further action on policy uptake.
Chagas disease (CD)
Benznidazole for the treatment of patients in the
late indeterminate or early chronic phase of T.
cruzi infection.
Principal Investigator: Dr Carlos A. Morillo,
Professor, Department of Medicine, Director
Arrhythmia Service, Cardiology Division, McMaster
University, Population Health Research Institute,
Hamilton, Ontario, Canada.
Patients with documented Chagas infection
determined by a positive T. Cruzi serology test
have a 2030% chance of progressing to dilated
cardiomyopathy. The role of antitrypanozomal
therapy to prevent this progression has been
suggested in observational studies. However, this
hypothesis has not been tested in a double-blinded
placebo controlled intervention trial. Because
chronic Chagas disease may indeed be triggered
by persistent parasitic infection, it appears
plausible that therapy with an antiparasitic agent
may delay or reduce the progression of chronic
CD. These recent ndings raise the exciting
possibility that antitrypanosomal therapy in the
BL6
33
TDR BL6 2009 Report
chronic stage of Chagas disease can eradicate the
parasite and prevent the progression to end stage
cardiomyopathy and death.
The study BENznidazole Evaluation For
Interrupting Trypanosomiasis trial (BENEFIT) is
the largest clinical trial conducted in Chagas disease
ever with 37 active centres and plans to recruit
further centres from Peru and the Plurinational
State of Bolivia. It is a double-blind placebo
controlled randomized clinical trial that will test the
hypothesis that in patients with evidence of chronic
Chagas heart disease, treatment for 60 days with
benznidazole will reduce the rate of clinical disease
progression (BENEFIT FULL) and reduction of T.
cruzi in the blood (BENEFIT PILOT). Polymerase
Chain Reaction (PCR) technology will be used to
determine the rate of negativization after active
therapy. PCR technique has been standardized and
samples are analysed in three core laboratories
located in Argentina, Brazil and Colombia. Samples
are collected at baseline, after completing therapy at
60 days and at the end of follow up at three years.
The study is on track, with 770 patients from
Argentina, Brazil and Colombia in 37 centres
having been randomized. Further patients
from Peru and the Plurinational State of Bolivia
will be included. Safety and tolerability issues
have been lower than the expected rates (fewer
safety issues than usually mentioned). Samples
for quantitative and qualitative PCR analysis
for efcacy have been drawn and are being
processed by the core laboratories in Argentina,
Brazil and Colombia.
The study protocol had to be amended
for drug dosage and regimen because the
new manufacturer (Brazils Laree) changed
formulation to non-scored tablets, preventing the
use of the recommended 5mg/kg dose.
Delayed due to change in product formulation.
Leverage
Canadian Institute of Health Research support not
renewed in 2009.
Continuation of enrolment and patient follow up as
per work plan.
Once the BENEFIT pilot is nished (2010), TDR
will have to consider the role it wants to play in the
progression of the BENEFIT full study.
Objective 2b: Pharmaco-epidemiology in
support of disease control
NEW: Pharmaco-epidemiology/vigilance in
community directed interventions
TDR project manager: Mr Olivier Lapujade.
A pharmaco-epidemiology approach to neglected
tropical diseases is being developed with expert
assistance. A partnership is being created including
the London School of Hygiene and Tropical
Medicine to develop this area.
Objective 2c: Markers and methods of
evaluation of treatment effects
NEW Activity: Research for molecular markers
of O. volvulus response to ivermectin and
development of an ivermectin response
surveillance tool
Investigators who submitted proposals:
Dr S. Wanji, Research Foundation for Tropical
Diseases and the Environment, Cameroon (in
collaboration with Dr J. Kamgno, (Coalition des
34
TDR BL6 2009 Report
BL6
ONGD Internationales contre lonchocercose)
and Dr M. Boussinesq, IRD, France).
Dr D. Boakye, Noguchi Memorial Institute
for Medical Research (NMIMR)/ Council for
Scientic and Industrial Research (CSIR), Ghana.
Dr W. Grant, La Trobe University, Australia.
Dr R. Pritchard, McGill University, Canada.
(a proposal had also been requested from Dr L. Toe,
Multi Disease Surveillance Centre, Burkina Faso,
but was not submitted).
Project Manager: Dr Annette Kuesel
Until 2006, TDR-supported clinical and molecular
biology research conducted in Australia and Canada
aimed at identifying genotypic changes associated
with the repeated use of ivermectin. Changes were
identied on the -tubulin, ABC transporters,
GABA and Glucls genes, as well as some other 35
anonymous markers. None of these changes were
validated as ivermectin resistance markers, since a
resistant phenotype had not been identied.
Since 2006, data have become available which show
that in some individuals the microlaria respond
to ivermectin as expected, but skin microlaria
levels increase earlier and faster than expected
based on historical data. The onchocerciasis control
programmes have recognized these observations as
warning signs of potentially changing response of
O. volvulus to ivermectin. The African Programme
for Onchocerciasis Control (APOC) has asked TDR
to re-initiate research to identify, and if applicable
validate, markers of response to ivermectin; to
develop a tool suitable for routine surveillance of
response to ivermectin and to build infrastructure
and personnel capacity in three African laboratories
as well as the Multi Disease Surveillance Centre to
conduct the genetic analysis of samples obtained at
APOC surveillance sites.
The Noguchi Institute in Ghana, the Research
Foundation for Tropical Diseases and the
Environment in collaboration with the Centre
de Recherche sur les Filarioses in Cameroon, as
well as the Multi Disease Surveillance Centre in
Burkina Faso were identied in March 2009 by
the Technical Consultative Committee (TCC)
of APOC as research centres which should have
capacity built. In October 2009, a joint workplan
was submitted to TDR by the four investigators
listed above. The proposal is currently undergoing
evaluation by the SPT.
Project implementation versus plan
The initiation of the project was later than planned
due to a delay in identication of the African
laboratories originally assigned in 2008 by APOC to
TABLE 11. BUDGET TO FINALIZATION OF PROJECT
a
ON IN US$
2010* 2011* 2012* 2013** 2013**
Laboratories in Australia, Canada 279 712 287 116 304 299 250 000 250 000
African laboratories 571 418 413 002 450 474 350 000 350 000
Sum 851 130 700 118 754 773 600 000 600 000
a
Research for molecular markers of O. volvulus response to ivermectin and development of an ivermectin response surveillance tool
* Budgets submitted by the investigators in 2009 currently undergoing evaluation by the Special Project Team, ** TDR estimate
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TDR BL6 2009 Report
TDR. In March 2009 the APOC TCC identied the
three laboratories in Africa already listed.
Specic activities in 2010
Initiation of research activities pending approval by
the SPT.
Transdermal delivery of diethylcarbamazine-
citrate (DEC patch) as a diagnostic tool for
onchocerciasis (completed)
TDR project manager: Dr J. Lazdins, Dr J. Remme
(to 2008), Dr A.C. Kuesel.
Principal Investigators: Dr K. Awadzi, Onchocerciasis
Chemotherapy Research Centre, Ghana (clinical
studies); Dr L.Diawara, Ministre de la Sant et de
la Prvention Mdicale, Senegal; Dr M.O. Traore,
Direction Nationale de la Sant, Mali (eld studies).
The objective of this project was to provide to
the African onchocerciasis control programmes
a non-invasive tool for large scale surveillance
for residual or re-emerging onchocerciasis. Based
on TDR sponsored clinical and eld studies of a
transdermal delivery technology based DEC patch,
in 2008 the APOC TCC recommended the use of the
DEC patch for onchocerciasis surveillance based on
the clinical and eld data generated by these studies
in the same year. APOC is now following up with
endemic countries for approval of DEC patch use.
APOC asked HNR in 2009 to support APOC by
coordinating and providing technical input for
the negotiation of the legal agreement between
WHO and the DEC patch manufacturer (Lohmann
Therapie Systeme) for an at-cost provision of the
DEC patch to WHO. These negotiations are ongoing.
Negotiation with Lohmann Therapie Systeme
ongoing.
Leverage
Development and production of a DEC patch by
Lohmann Therapie Systeme.
Validation and standardization of clinical research
use of polymerase chain reaction (PCR) for
detection of T. cruzi (completed as originally
planned, follow on project initiated)
Principal Investigator: Dr Alejandro G. Schijman,
LabMECh, INGEBI-CONICET, Buenos Aires,
Argentina.
TDR project manager: Dr Janis K. Lazdins-Helds
(new manager to be appointed).
This project aimed at standardizing PCR
methodology for diagnosing T. cruzi infection in
clinical research.
Application and utility of PCR technology in clinical
research and management has been limited, mainly
due to the differences in methodology which makes
comparisons of results among centres difcult
or impossible. Following a request from key
investigators from Argentina, Brazil and Colombia,
TDR sponsored an INGEBI-CONICET, Buenos
Aires-coordinated initiative to standardize the use
of PCR for analysis of clinical samples. Twenty nine
centres from all over the world participated.
This project was completed as planned in
2008 providing a standardized PCR protocol
for diagnosing T. cruzi infection. In 2009, the
groundwork for validation of this protocol in other
settings and stages was laid.
Leverage
TDR sponsoring leveraged additional funding from
Consejo Nacional de Investigaciones Cienticas y
Tecnicas (Argentina), the United Nations University
and Fundacion Bunge y Born (Argentina).
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TDR BL6 2009 Report
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The PCR methodology developed will be validated
in other settings and stages of infection.
Revised dengue classication and updated case
management guide
Principal investigators: Dr Lucy Lum, Malaysia;
Dr Efren Dimaano, the Philippines; Dr N.Hung,
Viet Nam; Dr J.Farrar, Viet Nam/United Kingdom;
Dr Siripen Kalayanarooj, Thailand; Dr Khampe
Phomgsavath, Lao Peoples Democratic Republic;
Dr Eric Martinez, Cuba; Dr Elci Villegas, the
Bolivarian Republic of Venezuela; Dr Joao Siqueira,
Brazil; Dr Ivo Castelobranco and Dr Tomas Jnisch,
Germany; Dr Angel Balmaseda, Nicaragua; Dr Eva
Harris, USA; Dr E. Pleites, El Salvador; Dr Gladys
Ramirez, Peru; Dr Carmen Soria and Dr Lyda
Osorio, Colombia; Dr Jose G. Martinez, Mexico.
TDR project manager: Dr Axel Kroeger
Dengue disease was classied in the early 1970s,
based on the experience of Bangkoks Children
Hospital, into three categories: dengue fever,
dengue hemorrhagic fever and dengue shock
syndrome. However, clinicians have had difculties
using this classication, citing its rigidity and focus
on hemorrhagic manifestations. TDR organized
a meeting of dengue clinicians in 2003 in Cuba,
commissioning a systematic literature review about
the actual use of the classication and organizing
a prospective clinical multi-centre study in seven
countries in Asia and Latin America.
Over a period of 10 months, 2261 patients were
enrolled; of these, 1724 patients had a full data set and
were conrmed dengue cases or highly suggestive.
Clinical management by experienced dengue
physicians, care level and type of medical interventions
were used as criteria for distinguishing between three
levels of severity. Laboratory parameters, as well as
clinical signs and symptoms, were analysed for their
association with different levels of disease severity.
The statistical analysis showed that there was a clear
distinction between severe and non-severe dengue.
Additionally, warning signs associated with severe
disease were established.
An international clinical expert group reviewed
all this evidence and suggested a new, three-level
severity classication which would be more
suitable for triage and clinical management. This
consists of: severe dengue, dengue with warning
signs and dengue without warning signs. This
revised classication is being validated in clinical
settings of 18 countries in 2009. Interim results
showed a highly consistent agreement by dengue
physicians to adopt the revised classication
because of user-friendliness, decision support for
clinical management and triage particularly in
outbreak situations. Three countries adopted the
revised classication in their national guidelines.
Interim results were discussed in Cuba with dengue
clinicians from 14 Latin American countries.
After 4 years of work, the TDR-supported multi-
centre clinical study (Denco, Dengue Control) has
generated an evidence base for proposing a new
classication of dengue disease into three levels
of severity: severe dengue, dengue with warning
signs and dengue without warning signs.
Clinical and laboratory criteria have been
assessed and their sensitivity/specicity
for correctly classifying dengue has been
determined.
TDR conducted an expert meeting of dengue
clinicians (October 2008) resulting in a proposal
for revised treatment guidelines.
TDR coordinated the development of a model
slide series for training, a yer for daily use in
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TDR BL6 2009 Report
clinical practice and a ow chart for wall posters
in reception areas for dengue patients.
TDR organized a clinical validation study in 18
countries comparing the revised classication
and clinical management with the previous one.
On track.
Leverage
The DENCO clinical project was nanced by the
European Union with roughly US$ 500 000 and
an additional US$ 100 000 from the Wellcome
Trust. TDR contributed roughly US$ 200 000.
The validation study was nanced by ministries of
health, TDR (US$ 90 000) and the Wellcome Trust.
Joint analysis of a TDR-coordinated validation
study of the revised dengue case classication
and modied case management guidelines in 18
countries in an international expert meeting in
Saudi Arabia in March 2010. Production of clinical
management guidelines together with the WHO/
NTD Department.
NEW ACTIVITY: Standardization of methods for
diagnosis and evaluation of treatment effect in
cutaneous leishmaniasis
TDR and NTD project manager: Dr Piero L. Olliaro
and Dr Jorge Alvar.
TDR and WHO/NTD have jointly organized a
workshop entitled Standardization of Methodology
for clinical studies of cutaneous leishmaniasis to
discuss the methodology of clinical trials aimed
at assessing interventions for treating cutaneous
leishmaniasis with the objective of informing WHO
guidelines (1517 December 2009).
Anthropometric database on patients with visceral
leishmaniasis (VL) from different endemic areas
Investigators: Michael Harhay (University of
Pennsylvania, USA); Manica Balasegaram (DNDi,
Switzerland); Michel Valliant (CRP-Sant,
Luxembourg); Franois Chappuis (Mdecins Sans
Frontire [MSF], Switzerland); Angeles Lima (MSF,
Spain); Koert Ritmeijer (MSF, the Netherlands);
Dorcas Lamounier Costa (Federal University of
Piau, Brazil); Suman Rijal (B P Koirala Institute of
Health Sciences, Nepal); Shyam Sundar (Banaras
Hindu University, India).
TDR project manager: Dr Piero L. Olliaro
There is no available data on the basic
characteristics (age, weight, sex) of patients with
VL except limited series. A worldwide database will
help adapting dosages and projecting drug volumes
and costs.
Cochrane systematic reviews and meta-analysis of
drug for treating schistosomiasis
Investigators: Dr Anthony Danso-Appiah, Dr Juerg
Utzinger, Dr Paul Garner.
A systematic review of treatments for urinary
schistosomiasis completed and published, one
on S.mansoni under way. Systematic reviews are a
powerful tool to inform policy and research.
Projects initiated prior to 2008 with commitments
to subjects and investigators which are being
continued to nalization
Human African trypanosomiasis (HAT)
New nifurtimox and eornithine regimen for the
treatment of stage 2 HAT
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TDR BL6 2009 Report
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Principal Investigators: Dr Freddie Kansiime, Omugo
health centre, Omugo, Uganda, and Dr Seraphine
Adibaku, Moyo District Hospital, Moyo, Uganda.
TDR project manager: Mr Olivier Lapujade
A clinical study comparing the efcacy and safety
of a 10 day nifurtimox-eornithine combination
treatment regimen with the standard 14 day
eornithine regimen for the treatment of T.b.
gambiense human African trypanosomiasis in the
meningo-encephalitic phase, was initiated in two
TDR sponsored clinical trial sites in Uganda in
2005. A total of 109 patients were recruited at these
two sites and the follow up of these patients was
completed in June 2009. The database was frozen
in mid-December 2009 after cleaning the data.
The statistical analysis and study report will be
available in the rst quarter of 2010.
The combination treatment has already been
included in the Essential Drugs List based on
data generated by DNDi and Epicentre. NEC
will advance the approach to disease control and
management by:
reducing the hospital admission period for
patients;
reducing the intensity of the nursing care
required;
improving acceptability of the treatment;
reducing costs associated with long
administration of infusion and prolonged
admission of patients;
may reduce the probability of emergence of
resistance against the individual drugs.
Recruitment completed 109 patients recruited.
Follow up completed in June 2009.
Clinical trials facilities and equipment in Omugo
were handed over to the health centre at the end
of recruitment.
Empowerment of two teams (in Omugo and
Moyo), through participatory training to
attain the skills of international quality for the
conduct of Good Clinical Practice clinical trials.
Translation of the principles and knowledge
learned during the conduct of the study to the
general patient care activities, especially the
nursing care.
Preparation of an interim in-hospital safety
data report.
The study provides patient treatment since at
the time there were no disease control activities.
The study is increasing community awareness of
the disease.
Delayed due to slow recruitment.
Leverage
Funding for the study provided by sanof-aventis.
Donation of the two drugs for clinical trial by
Bayer Healthcare AG and sano-aventis through
WHO NTD Department.
Logistical support within the country from the
WHO country representative in Uganda and
national control programme.
Collaboration with multi-site sponsorship of
the study by TDR (Uganda), DNDi (Democratic
Republic of the Congo) and MSF (the Congo,
Brazzaville).
Statistical analysis and study report.
DNDi agreed on a meta analysis including DNDi
and TDR data.
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TDR BL6 2009 Report
Nifurtimox-Efornithine Combination Therapy
was included in the Essential Medicines List in
May 2009 based on a le submitted by DNDi.
TDR data are intended to complement this dossier.
Present the report to the Ugandan Ministry
of Health as evidence for the policy decision-
making process.
Address research needs highlighted above.
Three-day pentamidine treatment regimen for 1
st

stage HAT
Principal Investigators: Dr Jimmy Opigo, Moyo
District Local Government, Moyo, Uganda and
Dr Bernard Opar, Adjumani Hospital, Adjumani,
Uganda.
TDR project manager: Mr Olivier Lapujade
The study Assessing three-day pentamidine for
early stage human African trypanosomiasis,
started in February 2008 in Adjumani and Moyo
(Uganda). The hypothesis is that a three-day
pentamidine regimen can achieve cure rates for
early stage T.b. gambiense equivalent to those of
the current 7 to 10-day regimen. This hypothesis
is based on recent pharmacokinetic information
on pentamidine showing a prolonged elimination
period, thus keeping the drug at therapeutic
levels for over 29 hours after a single parenteral
administration.
Availability of a shorter regimen with pentamidine
may not only reduce adverse effects but also reduce
treatment costs to the health systems and be more
convenient for the patients.
Recruitment started at a low rate, but increased
later. As of August 2009, approximately100
patients had been recruited.
The sample size has been recalculated and reduced.
The teams have developed very effcient case
nding strategies and Standards of Practice
(SOPs), which is an improvement from the
traditional methods. These new SOPs will be
introduced to the control programmes as a
capacity strengthening effort for surveillance.
A third site has been initiated with the same
Principal Investigator Dr Jimmy Opigo, and
expected recruitment of: 60 patients within
1 year with active case detection).
Delayed due to subject recruitment being slower
than anticipated and delay in provision of funds
to the site.
Leverage
Funding for the study given by sanof-aventis
(designated funds).
Logistical support within Uganda from the
WHO country ofce and the national control
programme.
Continue recruiting in Uganda and follow up of
enrolled patients (monitoring, data management) as
per project work plan.
Consider additional trial site to speed-up
recruitment
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TDR BL6 2009 Report
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4.1 Leverage
This has been addressed in Section 3 by strategic
objective and activities.
4.2 Contribution to overall
capacity building and
stewardship activities
The major of capacity-building activities conducted
by HNR in 2009 were:
Infrastructure and personnel capacity built
for three new clinical research centres in the
Democratic Republic of the Congo (2) and
Liberia (1), (for moxidectin development).
Continuing course-based training of new clinical
monitors from the Democratic Republic of the
Congo, Ghana and Liberia, on-the-job training of
new clinical monitors in the Democratic Republic
of the Congo and Liberia by experienced clinical
monitors (for moxidectin development).
Support of national clinical researchers from
endemic countries to generate evidence to
reassess treatment guidelines (dengue).
Details and information on additional capacity
building by HNR are provided in sections 3.1.2
(Table 5) and 3.1.3 (Table 6).
4. Leverage and contribution
to empowerment and
stewardship
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TDR BL6 2009 Report
HNR stafng. HNR stafng is insufcient to carry
out the assigned activities essentially because
some work on projects is assigned to another
unit. This negatively affects the capacity of HNR
to address the new areas that have been identied
while continuing to look after current projects.
To ensure that all projects have sufcient
professional and general administrative staff to
ensure the required level of project management
and administration consistent with the objectives
and timelines of the projects, four full Professional
staff (full-time employees) and three General
administrative staff are needed.
Financial resources. The available budget in 2009
was 76% of the revised approved budget, and 82%
of the expenditures went to moxidectin. The funds
for moxidectin and other onchocerciasis/LF related
activities are designated which are in principle
unaffected by cash ow problems like the one
experienced in the second semester of 2009.
The combination of limited nancial and human
resources means that new activities identied by
the SAC cannot be taken up unless signicant
delays in ongoing projects are incurred or personnel
resources from outside TDR can be engaged without
signicant costs.
In this context, HNR has adopted innovative
approaches. Some activities (e.g. the VL
anthropometric database) are conducted with no
funds, making the best of HNR internal expertise,
networking and convening power, whereby
investigators and other institutions contribute data,
work (i.e. salaries), and expertise on an equal basis.
Another approach being discussed is farming out
activities related to the preparation of frameworks
such as that for development of pharmaco-
epidemiological methods for use by NTD control
programmes (with external collaborators and other
organizations such as the LSTMH). The extent to
which this can be done depends on the amount of
nancial resources available.
5. Critical issues
and suggested solutions
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TDR BL6 2009 Report
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6. Annexes
6.1 Overview of Moxidectin Development Plan and Status
2006 2008 2010 2015
Consultation
with EMEA
Consultation
with EMEA
Consultation
with EMEA
Consultation
with UK and
French Regulators
Phase 2 study
Phase 3 study
Community studies
Studies conducted by WHO/TDR
Studies conducted by Wyeth
Pediatric study
Preclinical studies
Healthy volunteers
- Food eect
- Milk excretion
- Drug interaction
Chemistr y Manufacturing Control (Quality)
Decision
to initiate
Phase 3 study
Decision to initiate
IV M year of
communities studies
Decision to submit
dossier for EMEA
scientic opinion
Decision to submit
dossier to RA of
endemic countries
Decision for review
by WHO Expert
Committee
Decision to initiate
Mox year of
community studies
WHO Expert Review
Implementation into
control programmes
Grey box indicates delay in initiation of Phase 3 study relative to plans in the HNR business plan which has implications on all following
activities which are based on Phase 3 data.
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TDR BL6 2009 Report
6.2 List of publications from HNR-funded
or HNR-managed research
Belizario VY et al. Efcacy and safety of 40 mg/kg and 60 mg/kg single doses of praziquantel in the
treatment of schistosomiasis. Journal of Pediatric Infectious Diseases, 2008, 3:27-34.
Danso-Appiah A et al. Drugs for treating urinary schistosomiasis. Cochrane Database of Systematic Reviews,
2008, 16;(3):CD000053.
Danso-Appiah A et al. Treatment of urinary schistosomiasis: methodological issues and research needs
identied through a Cochrane systematic review. Parasitology, 2009, 136(13):1837-49.
Farrar J et al. WHO/TDR Dengue Scientic Working Group. Towards a global dengue research agenda.
Tropical Medicine & International Health, 2009, 12(6):695-699.
Geary TG et al. Unresolved issues in anthelmintic pharmacology for helminthiases of humans.
International Journal of Parasitology, 2009, 40(1):1-13.
Marin-Neto JA et al. Rationale and design of a randomized placebo-controlled trial assessing the effects
of etiologic treatment in Chagas cardiomyopathy: the BENznidazole Evaluation For Interrupting
Trypanosomiasis (BENEFIT). American Heart Journal, 2009, 156:37-43.
Olliaro P, Sundar S. Anthropometrically derived dosing and drug costing calculations for treating visceral
leishmaniasis in Bihar, India. Tropical Medicine & International Health, 2009, 14(1):88-92.
Olliaro P et al. Cost-effectiveness projections of single and combination therapies for visceral leishmaniasis in
Bihar, India. Tropical Medicine & International Health, 2009,14(8):918-925.
Runge-Ranzinger S et al. What does dengue disease surveillance contribute to predicting and detecting
outbreaks and describing trends? Tropical Medicine & International Health, 2008, 13:1022-1041
Santamaria R et al. Comparison and critical appraisal of dengue clinical guidelines and their use in Asia and
Latin America. International Health, 2009, 1, 133-140.
Shenoy RK et al. Anti-larial drugs in doses employed in Mass Drug Administration (MDA) by the Global
Programme for Elimination of Lymphatic Filariasis (GPELF) reverse lymphatic pathology in children with
Brugia malayi infection. Annals of Tropical Medicine and Parasitology, 2009,103:235-247.
Shenoy RK et al. Relevance of anti-BmR1 IgG4 antibodies in children from an area endemic for Brugia malayi
infection in Kerala, India. Journal of Communicable Diseases, 2009, (in press).
44
TDR BL6 2009 Report
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6.3 SAC membership
Dr Shally Awasthi, Professor of Pediatrics, Department of Pediatrics, King Georges Medical University,
Lucknow, Uttar Pradesh, INDIA
Dr Jeremy Farrar, Director, Oxford University Clinical Research Unit, The Hospital for Tropical Disease,
Ho Chi Minh City, VIET NAM
Dr Lon Kazumba, Centre Neuro-Psycho Pathologique, CNPP/CUK, Chef dUnit de la THA, Departement
de Neurolgie, Kinshasa, DEMOCRATIC REPUBLIC OF THE CONGO
Dr Edward Greg Koski, Associate Professor of Anesthesia, Harvard Medical School, Senior Scientist,
Institute for Health Policy, Massachusetts General Hospital, Department of Anesthesia and Critical Care,
32 Fruit Street, Boston, Massachusetts, USA
Dr Thomas B. Nutman, Head, Helminth Immunology Section and Head, Clinical Parasitology Unit,
Laboratory of Parasitic Diseases, Building 4, Room B1-03, 4 Center Drive, National Institutes of Health,
Bethesda, MD, USA
Dr Ana Rabello (Chair person), Ren Rachou Research Center, Oswaldo Cruz Foundation, Laboratory of
Clinical Research, Avenue Augusto de Lima, 1715 Barro Preto, Belo Horizonte, Minas Gerais, BRAZIL
Dr Mamadou Souncalo Traor, DER de Sant Publique, Facult de Mdecine de Pharmacie et DOdonto-
Stomatolige (FMPOS), Bamako BP E810, MALI
Dr Nana Twum-Danso, Director, Project Fives Alive!, IHI/NCHS Partnership for Reducing Child Mortality in
Ghana, National Catholic Secretariat, Department of Health, Accra, GHANA
Dr Jennifer Keiser, Medical parasitology and infection biology, Swiss Tropical Institute, Basel,
SWITZERLAND
Dr Taner VARDAR, Autoimmune Diseases and Emerging Therapies, Medical Safety Group, Global Drug
Safety, Merck Serono International S.A, Geneva, SWITZERLAND.
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TDR BL6 2009 Report
6.4 HNR projects, end
products and expected
outcomes
Objective 1: Development,
registration and field evaluation
of new products for NTDs (new
drugs for NTDs)
Objective 1a) New drugs for onchocerciasis,
lymphatic lariasis, soil-transmitted
helminthiasis, schistosomiasis, foodborne
trematodes and dengue
Moxidectin for onchocerciasis (and lymphatic
lariasis)
End product (ongoing): (i) clinical data from Phase
2 and 3 trials to assess whether moxidectin meets
target product prole for registration (2011); (ii)
community study data on effect on onchocerciasis
transmission and safety during mass treatment
(2015).
Outcomes: (i) ling by manufacturer for
registration; (ii) EMEA scientic 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
elimination of onchocerciasis as a public health
problem to eradication of infection.
L-praziquantel for schistosomiasis
End product (ongoing): data to assess whether
enantiopure L-praziquantel meets target product
prole for registration (2015).
Outcomes: (i) ling by manufacturer for registration
and/or list of essential drugs; (ii) registration/
adoption by concerned endemic countries.
NEW ACTIVITY: Drug development candidates
for helminths and dengue
End product (ongoing): a dossier on each potential
candidate, expert evaluation of each potential
candidate with recommendation on transition into
pre-clinical or clinical development.
Outcome: Initiation of preclinical or clinical
development, if indicated (with or without HNR
direct involvement).
Objective 2: Generation of evidence
for improved use of currently
available drugs (treatment
optimization and biomarkers)
All NTDs all sub-objectives within
NEW ACTIVITY: Dossiers on drugs currently
used for NTDs
End product (ongoing):
Comprehensive compilation of non-clinical and
clinical data publicly available for each drug used
for treatment of NTDs (20102012).
Assessment of dossiers by experts for identication
of particular risks for agging to disease control
programmes, for informing design of studies to test
and optimize systems for pharmaco-epidemiology/
pharmacovigilance for NTDs and potential
identication/prioritization of HNR research
(20102013).
Outcome: Identication of research questions for
treatment optimization studies, risk management
plans established by WHO disease controls
programmes and/or national disease control
programmes.
46
TDR BL6 2009 Report
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Onchocerciasis/lymphatic lariasis/loa loa
Therapeutic effect of albendazole +
lymphatic lariasis
End product (ongoing): Clinical evidence of
the safety and efcacy in curing and reversing
lymphatic lesions in children infected with Brugia
malayi (2009 / 2012).
Outcome: Lymphatic lariasis control programmes
to include cure of infection and regression of early
lymphatic lesions in children (currently aiming only
at interruption of transmission).
Evaluation of the efcacy of albendazole in
reducing loa loa microlaremia
End product (completed): Proof of concept of
efcacy of albendazole against loa loa (2009).
Outcome: If positve, accelerated expansion of
the use of ivermectin against onchocerciasis and
implementation of ivermectin + albendazole treatment
in lymphatic lariasis loiasis co-endemic zones.
Schistosomiasis
Combination of praziquantel and oxamniquine
for schistosomiasis.
End product (ongoing): Data to assess the merits
of drug combination for schistosomiasis treatment
(2011).
Outcome: If positve, adoption by schistosomiasis
control programme as a means to prevent
emergence of drug resistance.
Effective and safe dose of praziquantel for the
treatment of schistosomiasis
End product (ongoing): Data to assess the
safety and efcacy equivalence of 40 mg and
60 mg doses of praziquantel for the treatment of
schistosomiasis (2009).
Outcome: Use by WHO and national
schistosomiasis control programmes for decision on
dose to be used.
schistosomiasis
End product (ongoing): evidence base for research
and treatment policy recommendations for
schistosomiasis (2010).
Outcome: use of results to inform research priority
setting and treatment recommendations.
Leishmaniasis
Anthropometric database on patients with visceral
leishmaniasis from different endemic areas
End product (ongoing): an anthropometric database
of patients with VL from all endemic regions.
Outcome: use of results to inform general and
country-tailored drug procurement strategies and
complementary interventions (e.g. nutritional).
Chagas disease
Benznidazole for the treatment of patients in the
late indeterminate or early chronic phase of T.
cruzi infection
End product (ongoing): Safety and efcacy
(clearance of parasites PCR) in the chronic phase
of T. cruzi infection in BENEFIT pilot (2010).
Outcome: Contribute to a large multicentre study
titled BENEFIT to demonstrate the reduction of
the risk of cardiac disease onset and progression
in T. cruzi infected individuals after treatment with
benznidazole. If results are positive, this will result
in a change of treatment guidelines.
TDR/World Health Organization
20, Avenue Appia
1211 Geneva 27
Switzerland
Fax: +41 22 791-4854
tdr@who.int
www.who.int/tdr
The Special Programme for Research and Training in Tropical
Diseases (TDR) is a global programme of scientic collaboration
established in 1975. Its focus is research into neglected diseases
of the poor, with the goal of improving existing approaches and
developing new ways to prevent, diagnose, treat and control
these diseases. TDR is sponsored by the following organizations:
World Bank

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ANNUAL REPORT 2009

TDR BUSINESS LINE 6

Onchocerciasis/LF Moxidectin for onchocerciasis (and

Onchocerciasis/LF Moxidectin for onchocerciasis (and

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