6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
Priority Medicines for Europe and the World
"A Public Health Approach to Innovation"
Background Paper
Analysis of Pharmaceutical Development Issues
for Malaria as Basis for Priority-Setting
L Riopel, Ph.D
Medicines for Malaria Venture
18 October 2004
6.10-1
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
Table of Contents
Summary................................................................................................................................................ 3
Introduction/Background .................................................................................................................... 4
Size and Nature of the Disease Burden (8,11-14) ................................................................................... 5
Malaria in endemic area ...................................................................................................................... 6
Malaria in non-endemic area ............................................................................................................ 12
A) Autochthonous (Indigenous) .................................................................................................. 12
b) Imported Malaria....................................................................................................................... 13
Control Strategy .................................................................................................................................. 14
Vector Control ..................................................................................................................................... 15
Case Management .............................................................................................................................. 16
Vaccines ............................................................................................................................................... 24
Why does the disease burden persist? What can be learnt from past and current research? . 25
What is the current pipeline? ............................................................................................................ 30
Development Projects .................................................................................................................... 30
Discovery Projects .......................................................................................................................... 31
Opportunities for research and what are the gaps between current research and potential
research issues..................................................................................................................................... 33
Conclusions and Recommendations................................................................................................ 35
References ............................................................................................................................................ 37
Appendix
6.10-2
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
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Summary
The worldwide resurgence of malaria is now well recognized. The sub-Saharan Africa bears
the burden of the disease with over one million deaths and up to 500 million cases annually,
affecting mostly young children and pregnant women. The social and economic costs of
malaria are immense and hamper peoples’ lives and perpetuate underdevelopment. Malaria
silently kills 3,000 children every day because access to preventive tools or basic treatment is
lacking. Resistance has rendered the old and cheap treatments like chloroquine and SP
useless in most parts of Africa and South East Asia.
Despite these staggering statistics the global community has not placed malaria high enough
on the geopolitical agenda to mobilize the resources necessary to combat and prevent this
devastating disease. As drug resistance was emerging in the 1970-80s, the pharmaceutical
industry disengaged from innovative R&D in tropical disease as the cost of drug
development was on the rise and the market incentive was simply not there.
Artemisinin-based combination therapies (ACT) are effective and today, are considered the
best antimalarials in terms of efficacy and lower propensity to resistance. However, they are
far from being ideal drugs because of their relatively high cost and unknown safety features
in women of child bearing potential. Nevertheless, these are the best options in the
immediate and to address the cost problem, the US National Academies of Science (IOM)
recently published a report advocating annual subsidies of US$ 500 million annually to
purchase ACT as first line treatments in disease-endemic countries.
In order to address the cost problem and expand the access to effective antimalarials, new
alternative drugs to supplement and replace older drugs are urgently needed. Solutions to a
cost effective approach to innovative drug research and development are emerging from
public-private partnerships (PPP) such as the Medicines for Malaria Venture (MMV). With a
total expenditure of about US$ 60 Million over four years, MMV has 21 projects in its drug
portfolio and funding of at least 30 Million annually will be needed to achieve its mission of
delivering new effective and affordable antimalarials for the disease-endemic countries and
sustaining a pipeline of drugs to stay one-step ahead of drug resistance. This investment is
small compared with the estimated US$ 12 billion lost GDP annually in Africa and the
significant funding needed for ACT. However, the success of MMV and other PPPs involved
in drug development will also depend on the innovation in applied sciences. Public and
private sectors must redirect the research agenda to support transitional research geared
toward the development of new and reliable experimental models allowing rapid and costeffective screening of new drug candidates in order to progress them to clinical development
with less risk of failures. The outlook for new medicines to tackle neglected diseases is better
than it has been in decades. We must capitalize on this momentum and take advantage of the
current quantum leaps in science by applying them efficiently and effectively.
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6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
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Introduction/Background
Malaria is one of the most ancient and deadly infectious diseases. Many historians believe
that it was one of the key causes for the fall of the Roman Empire(1). A fatal periodic fever has
been associated with biting insects since the antiquity but it is only in 1880 that the French
scientist Laveran identified the protozoa Plasmodium, the causative organism of malaria(2).
Today, approximately 120 species of the protozoa of the genus Plasmodium have been
identified in the blood of mammals, reptiles and birds and are recognized by the presence of
two types of asexual division: schizogony in the vertebrate host and, sporogony in the insect
vector. Within the vertebrate host, schizogony is found within erythrocytes and in other
tissues (exo-erythrocytic schizogony). The parasites of humans are exclusively transmitted
by the anopheline mosquitoe. There are four human malarial parasites: the most pathogenic
form, P. falciparum; and three less pathogenic but relapsing forms, P. vivax, P. malariae and P.
ovale.(3)
Following the mosquito bite, sporozoites injected into the blood stream invade the liver
where they multiply. In vivax and ovale infection, the development is interrupted resulting in
a dormant form, the hypnozoite, from which the infection may relapse months later. After 710 days in hepatocytes, schizonts rupture, releasing merozoites which invade the erytrocytes,
where they develop through ring forms to trophozoites and finally multi-segmented
schizonts. Pathological processes in malaria are the result of the erythrocytic cycle. In the
case of P. falciparum, the process results in several changes in the morphology and physiology
of the infected red cell resulting in the host immunological responses to the parasite antigens:
stimulation of the reticulendothelial system, changes in regional blood flow and vascular
endothelium, systemic complications of altered biochemistry, anemia tissue and organ
hypoxia and marked systemic inflammatory response characterized by release of cytokines
such as tumour necrosis factor-α (TNF- α) and interleukins, 4) which together are responsible
for the fever and other flu-like symptoms of malaria. If not treated, P. falciparum can be fatal or
cause serious neurological sequelae.
Until after the end of World War II, malaria was endemic throughout much of southern
Europe and seasonal epidemics or outbreaks occurred as far north as Scandinavia. By 1970,
malaria transmission was virtually eradicated from the continent following intensive control
measures. However, the anopheline populations remain high in many countries, which pose
the risk of renewed transmission should the number of infected human hosts increase. In the
mid-1990's recrudescence of autochthonous (indigenous) malaria has been noted in many
countries of the continent, reaching a total of nearly 91,000 cases in 1995 in the countries of
the WHO European region. In addition, between 10,000 and 12,000 cases of imported malaria
are reported in the European Union each year, a figure large enough to constitute a public
health and economic burden on the countries into which malaria is imported. (5)
In the past century malariologists have made important achievements in epidemiology,
pathophysiology, treatment and control and in the new Millennium, using molecular
genetics, scientists have almost complete knowledge of the P. falciparum genome.(6) Despite
these achievements, malaria still claims over one million lives annually with an incidence
possibly increasing beyond 500 million cases each year.(7) Pregnant women and young
children in sub-Sahara Africa are the most affected, bearing 90% of the global disease
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6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
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burden. Plasmodium vivax, although regarded as less threatening than P. falciparum also
represents a significant health problem in many regions of the world with an estimated 70-80
million cases annually.(8) In developing countries malaria is a key contributor to social,
economic and intellectual impoverishment of these communities.(7,9) (See Appendix 6.10.4)
Malaria is a preventable and curable disease but eradication programs have failed in the
developing countries and control measures to stop the progression of this human and
economic burden are also not reaching the set goals. However, in the past few years, there
have been improvements in its political profile resulting in an increased funding for malaria
prevention and interventions. Antimalarial drugs with selective actions on the different
phase of the parasite life cycle have proved to be efficacious in the treatment or prophylaxis
of malaria but resistance has spread widely making many of these drugs useless. Newer
effective drugs such artemisinin-based combination therapies (ACTs) are now the
recommended first line treatment,(10) but with a price tag that is 10-20 times more than the
older drugs, they are unaffordable for the populations and governments of low income
countries.(9,10)
New safe, effective and affordable treatments must be developed urgently. However, drug
development is expensive and the pharmaceutical industry, lacking the market incentive, has
significantly diminished its R&D investment in malaria and other neglected diseases. New
approaches to develop safe and effective medicines are being implemented by various
public-private partnerships (PPP), the success of which will depend not only on funding but
also on the adequacy of the research agenda. This analysis will first provide the information
necessary to appreciate the devastating effect of the disease, and will highlight the areas of
research and development needed to roll back malaria globally.
Size and Nature of the Disease Burden (8,11-14)
Individuals exposed to P. falciparum in areas of stable transmission will alternate between
periods when they are infected with the parasites and those where they are uninfected. Most
individuals will, at some stages in their lives, develop an overt clinical response manifesting
in most cases by febrile events. Without prompt medical treatment, these clinical events may
progress to severe illness and death. However, the disease may naturally resolve or the
patient may be cured with an appropriate intervention. There are several morbid
consequences associated with each step of the disease process. Chronic, sub-clinical
infections may render an individual anemic or predispose to under-nutrition, conditions that
will influence the severity and outcome of other infections. Asymptomatic infection of the
placenta of a pregnant woman significantly reduces the weights of their newborn children.
Patients who survive a severe disease are likely to suffer from debilitating sequelae such as
spasticity, epilepsy or retinopathy. Behavioral disturbances and cognitive impairment are
now also recognized as major consequences of malaria.
(See Appendix 6.10.3)
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6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
Figure 1: The direct, indirect and consequential public health effects of P. falciparum
malaria in Africa (Source: Snow and Gilles 2002) (11)
Malaria in endemic area
The health impacts vary between countries and communities. In the absence of measures to
reduce transmission, the impact will depend upon factors such as acquired immunity, access
to effective case-management or host genetics.
There are several published reports on attempts to estimate the global burden of malaria,
more specifically on the burden of P. falciparum in Africa where the disease is recognized to be
a major obstacle to human and economic development.(9-15,17) (See Appendix 6.10.4)
Accurate statistics on malaria in Africa are difficult to collect and report because of the
enormity of the disease problem, the weakness of health information systems, and the fact
that the treatment of most malaria cases, as well as many deaths, occur outside the formal
health system.(12) It is therefore generally agreed that figures published are rough estimates
and that the precise number of fatal and morbid events will never be known. Table 1
summarizes the estimates of morbidity and mortality by WHO administrative region during
2001.
Recently, Snow et al (12) have re-analyzed the consequences of malaria in Africa using
empirical epidemiological measures of disability, morbidity and mortality risks in function
of age and malaria transmission. Consistent with the WHO estimates for year 2001, (15) Snow
et al, estimated 1,144,572 deaths directly attributable to malaria in Africa in year 2000 (Table
2). Estimates presented in Tables 1 and 2 confirm the frequently quoted figures of about 90%
of all malaria deaths in the world occur in Africa south of the Sahara mainly in children
under 5 years of age.
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6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
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Table 1: Estimates of malaria morbidity and mortality by WHO administrative region during 2001
(13,15)
Morbidity
Mortality
Total
396,676,285
1,123,764
Africa
South East Asia
Eastern Mediterranean
Western Pacific
The Americas
Europe
342,814,347
32,930,363
14,894,969
2,238,314
3,798,292
0
962,736
94,380
54,570
10,474
1,445
160
Table 2: Estimated malaria specific mortality (IQR range) during 2000
(Source: Snow et al) (12)
Southern Africa
malaria risk (Class
4)
Rest of Africa- low
stable/epidemic
risk (Classes 2+3)
Rest of
stable
Endemic
(Class 4)
Africarisk
0-4 years
5-14 years
15+ years
266
[164 - 430]
482
[297 - 779]
1’129
[695 – 1’824]
1’1877
[1’156 – 3’033]
57,688
32,588
49,079
139,355
684,364
[541,330
1,068,723]
182,113
[76,072
319,274]
136,863
[84,399
214,419]
1,003,340
[701,801 - 1,602,415]
-
Total
-
-
742,318
214,701
187,071
1,144,572
[541,494
– [76,369
– [85,094
– [702,957 – 1,605,448]
1,069,153]
320,053]
216,253]
__________________________________________________________________________
IQR = Interquartile range, which represents the range of values from the 25th percentile to the 75th
percentile, essentially the range of the middle 50% of the data. Because it uses the middle 50%, the IQR
is not affected by extreme values.
Classification of areas:
Class 1: no human settlement, or unsuitable climate for malaria transmission.
Class 2: populations exposed to marginal risks of malaria transmission, uncommon in an average
year.
Class 3: populations exposed to acute seasonal transmission with a tendency toward epidemics.
Class 4: populations exposed to stable, endemic malaria transmission. In southern Africa (Namibia,
Swaziland, South Africa, Botswana, Zimbabwe) Class 4 areas, malaria still poses a risk but its extent
and transmission potential are determined by aggressive vector control.
SOURCE: Snow et al, (2003)
6.10-7
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
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Pregnant women, whose placentas are invaded by the malaria parasite, are particularly
vulnerable to malaria. Infection with the parasite may cause various adverse consequences
for both the mother and the newborn. These effects include maternal anemia, placental
accumulation of parasites, low birth weight (LBW) from prematurity and intrauterine
growth retardation (IUGR), fetal parasite exposure and congenital infection and infant
mortality (IM). Most population-based studies were conducted in Africa where P. falciparum
transmission is high, while fewer studies are reported from Asia and the Americas. Steketee
et al, 2001(13) reviewed studies conducted in African populations between 1985 and 2000 and
have summarized the malaria population attributable risk (PAR) that accounts for both
prevalence of the risk factors in the population and the magnitude of the associated risk for
anemia (Table 3). They have estimated that each year 71,000 to 190,000 infant deaths are
associated with malaria infection in pregnancy. Antimalarial chemoprophylaxis, or
intermittent preventive treatment (IPT) during pregnancy has been shown to reduce the risk
of malaria infection and significantly increase the birth of healthy babies born to
primigravidae (first-time mothers).(16) However, access to drugs and IPT is still very limited,
hence, deaths remain high in sub-Saharan Africa.
Table 3: Summary of population attributable risk (PAR) estimates for P. falciparum malaria
in pregnant women (from Steketee et al, 2001 (14) and Snow et al, 2003)(12) and applied to expected
numbers of pregnancies in 2000 in areas outside southern Africa in risk areas class 3 & 4
(see legend Table 2) to estimate indirect mortality
Adverse event
Moderate
or
severe anemia
Low birth weight
Pre-term LBW
IUGR LBW
Infant mortality
Prevalence/incidence Risk estimate
PAR (%)
Fatal events 2000
Attribute to
malaria
1-20%
1.5-2.5
2-15
-
12-20%
1.4-1.8
8-14
-
3-8%
2.2-3.5
8-36
-
8-15%
1.7-5.5
13-70
-
105%
NA
3-8
71,000-190,000
The magnitude of the economic burden of malaria is poorly documented. One can assume
that the direct and indirect costs in treating and preventing the disease are large to the
governments and families. According to the Africa Malaria Report 2003(17) an average of 30%
of all outpatient clinic visits are for malaria and that 20% to 50% of hospital admissions are a
consequence of malaria. (See Appendix 6.10.1) Malaria was ranked 8th highest global
contributor in Disability Adjusted Life Year (DALY) and 2nd in Africa.(15) These estimates,
however, were based largely on deaths as direct cause of malaria infection and on data
available on morbid events following cerebral malaria. In their analysis of malaria burden,
Snow et al(12) have also examined events consequential to the disease-related events such as,
the consequences of clinical management including the immediate effects of adverse drug
reactions or long-term residual effects of acquired HIV infection through blood transfusion.
In addition, there are other life-long disabilities related to untreated clinical cases of malaria
such as the short and long term residual neurological impairments following cerebral
malaria. Table 4 summarizes the mortalities, morbidities and other events that should be
taken into account in the estimation of malaria burden. It is important to note the estimated
6.10-8
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
mortality directly associated to adverse drug reaction (ADR). Drugs such as chloroquine
(CQ) can be toxic at excessive doses but yet, the authors observed that CQ seems to have the
least documented ADR risk. If we assume a minimum risk of 1:20,000 subjects exposed to a
drug will result in a severe ADR of which 50% are fatal, approximately 4,700 ADR and 2,350
deaths associated with treatment could be expected each year among children living outside
southern Africa.12 Those surviving the ADR may suffer various degrees of severity of
hepatotoxicity, agranulocytosis and aplastic anemia which could require treatment for up to
6 months, assuming adequate medical management is available, which often is not the case.
Vivax malaria, while causing less fatal cases, is also a debilitating disease, resulting in
deleterious effects on personal well-being, growth and development and, causing economic
hardship at the individual, family, community and national levels. Most recent statistics
available on incidence are those prepared for the 1999 World Health Report and were based
on data obtained from the WHO regional offices between 1993 and 1998.
The global burden of vivax malaria is estimated to be approximately 70-80 million cases per
year. Outside of Africa where P. falciparum is most prevalent, P.vivax accounts for 50% of all
malaria cases. About 80-90% of P. vivax occurs in the Middle-East, Asia and the Western
Pacific; the remaining 10-15% occurs in Central and South America. The rarity of P. vivax in
Africa and more specifically in West Africa is linked to the prevalence of the Duffy negative
trait, an inherited red cell phenotype that lacks the receptor for invasion of the human red
cell by the merozoites of P. vivax. (8)
Populations living in endemic P. vivax areas where transmission is low to moderate do not
achieve a high level of effective immunity. This means that for each new infection, clinical
symptoms such as fever, body aches and headaches are likely to occur with various degree
of severity. However, after several malaria attacks, the clinical manifestation is much
attenuated.
P. vivax differs from P. falciparum not only in its pathogenicity but also in its transmission
strategy. In P. vivax, the mature and infective germ cell or gametocytes appear in the blood of
an infected person almost simultaneously with the asexual blood stage parasites before the
clinical threshold of a blood infection is reached, while the gametocytes of P. falciparum
emerge at least 10 days after the clinical threshold of an infection has been reached. This
difference has important consequences in the pattern of selection of resistance and control
strategy against these parasites. For instance, because vivax gametocytes are transmitted to
mosquitoes during the pre-symptomatic period of P. vivax blood infection and before drug
treatment, P. vivax will be less vulnerable to control by deployment of effective drug therapy.
(8) In addition, the latent hepatic stage of vivax make control by deployment of drug therapy
difficult as the time at which relapses will occur cannot be predicted.
With over one billion inhabitants potentially at risk of vivax infection, vivax malaria may
increasingly contribute to the public health burden of malaria globally and the need for
research in effective control strategy is warranted.(8, 13)
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6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
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Table 4: A summary of the burden of P. falciparum malaria - Africa during 2000 (Source
Snow et al, 2003)
(12)
0-4 years
5-14 years
15+ years
Total
Malaria
specific
mortality
Maternal mortality
attributed
to
malaria-anemia
Infant
mortality
attributed to malaria
during pregnancy
742,318
[541,494-1,069,153]
214,701
[76,369-320,053]
187,071
[85,094-216,253]
1,144,572
[702,957-1,605,448]
--
--
5,300
5,300
71,000-190,000
--
--
71,000-190,000
Fatal adverse drug
events
Fatal HIV risks from
blood
transfusion
used
to
manage
SMA
Premature mortality
of poorly managed
epilepsy developed
through
cerebral
malaria or complex
seizures
Role of infection on
anemia,
undernutrition and HIV as
indirect
mortality
effects
2,350
Unknown
Unknown
2,300
Unknown
5,300-8,500
Malaria
morbid
attacks (thousands)
Estimated number of
morbid
days
(thousands)
Neuro-cognitive
sequelae following
cerebral malaria
Hemiparesis
5,300-8,500
--
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
108,519
[64,240-163,982]
74,077
[48,514-120,577]
30,953
[21,284-40,067]
213,549
[134,322-324,617]
553,447
[327,624-836,263]
168,053
[110,572-265,852]
82,199
[56,220-196,757]
803,699
[494,416-1,298,872]
360-400
Unknown
360-400
770-860
Unknown
770-860
650-730
Unknown
650-730
300-330
Unknown
300-330
1,540-1,720
Unknown
1,540-1,720
7,000-7,800
Unknown
7,000-7,800
2,700-3,000
Unknown
2,700-3,000
Unknown
Unknown
Numbers
Quadriparesis/Severe
deficit
Hearing impariment
Visual impairment
Behavioral
difficulties
Language deficits
Epilepsy
Effects of infection
on
cognitive
performance
Unknown
Unknown
Estimating the costs of malaria is difficult because there is no consensus as to which
approaches or methodologies to employ to evaluate the economic burden. Recent work on
defining the economic costs of malaria appears in the report published by the Institute of
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6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
Medicine National Academy of Sciences.(9) (See Appendix 6.10.4) Effects of malaria at a
macroeconomic level include those on household living standards, demographics, human
capital, trade and foreign investment and, at a microeconomic level, the economic effects of
malaria were based on costs of household and government expenditures on prevention and
treatment as well as indirect costs associated to lost of wages resulting from incapacity to
work. The bottom line figure often quoted is that malaria represents an estimated
$US 12 billion lost in GDP in Africa.(9)
In absence of effective control measures the problem can grow even bigger as illustrated in
the recent work of Hay et al. (13) (See Appendix 6.10.2) Using summary procedures in
geographic information systems and endemicity maps, they have found that between 1900 to
2002 the area of human malaria risk has been reduced by around half, from 53% to 27% of
the Earth's land surface (Table 5). However, because the global human population has grown
geometrically, the number of people at risk have increased from 0.9 to 3 billion during the
same period. The authors estimate that at the turn of the 21st century, 48% of the global
population remains exposed to the risk of malaria, a situation that has deteriorated since the
early 1990s.
Table 5: Global population at risk from malaria from pre-intervention to 2010 (1900-2010)
(Source: Hay et al, 2004) (13)
Time
Global
population
Land area malarious
Countri
es at risk
Population exposed
Years
n
Km2
%
n
n
%
1900
1946
1965
1975
1992
1994
2002
2010
1 158 409 472
2 391 400 960
3 363 417 344
4 085 759 488
5 419 255 808
5 582 432 256
6 204 095 488
6 807 085 056
77 594 480
58 565 752
53 492 988
48 075 780
43 650 812
39 537 020
39 758 172
39 758 172
53-16
40-12
36-65
32-93
29-90
27-08
27-24
27-24
140
130
103
91
88
87
88
88
892 373 056
1 635 815 808
1 924 360 320
2 121 086 592
2 565 702 144
2 570 555 136
2 996 419 584
3 410 862 080
77-03
68-40
57-21
51-91
47-34
46-05
48-30
50-11
The area totals were generated using the maps of all-cause malaria risk distribution through time. The percentage of Earth
malarious was calculated from a total global land surface area of 145 975 899 km2. To estimate countries at risk territorial
designations for 2002 were used throughout (Environmental Systems Research institute, Inc, Redlands, California, USA).
Country-specific “medium variant” population growth rate from the World Population Prospects database
(http://esa.un.org/unpp) between 1950 and 2010 were applied to the Gridded Population of the World (GPW) v2.0 to generate
population distribution maps for 1900, 1946, 1965, 1975, 1992, 1994, and 2002 to match with the malaria risk distribution maps
and were also projected to 2010 to enable evaluation of potential future changes in global malaria risk. Global summary counts
of these population distribution maps give accuracy to within 5% of the UNDP global population estimate
(http://esa.un.org/unpp) for all calculated years. All area and population summaries from these polygons were processed in
Idris Kilimanjaro (Clark Labs, Clark University, Worcester, MA, USA).
____________________________________________________________________________
6.10-11
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
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Malaria in non-endemic area
To further appreciate the risk that lack of control could have on malaria and to provide some
insight to the potential economic burden in developed countries, it is worthwhile to examine
the malaria situation within the WHO European Region published in a recent report: The
vector-borne human infections of Europe- Their distribution and burden on public health. (5)
A) Autochthonous (Indigenous)
Autochtonous or indigenous malaria refers to cases that are transmitted locally by mosquito
species living in the area.
Italy



P. falciparum disappeared from Italy in 1950 while P. vivax persisted until 1955 (18)
Most of southern and rural Italy remains receptive to malaria transmission, due to the
presence of high density of An. labranchiae and other mosquito vectors. (19) However,
most of these species are not susceptible to the African strains P. falciparum.
In 1977, index case of malaria has been attributed to local anophelines infected with
exogenous P. vivax. (20)
The Netherlands
Last case of indigenous malaria was reported in 1960 (21)
 The Dutch malaria vector cannot transmit P. falciparum
 The only malaria vector in the Netherlands An Atroparvus is near extinction (22)
 Recrudescence of transmission due to increased mosquito population is possible but
not considered a threat given the current environmental conditions.
Spain

A case of locally transmitted P. ovale has been reported recently. (23) Because of the
proximity of the airport, it is speculated that a local An. labranchiae or An. atroparvous
may have bitten a gametocyte-carrying migrant worker.
Russian Federation & Moscow Region
 Malaria was endemic throughout the region until DDT vector program combined
with active case detection began in 1945.
 The number of imported malaria cases has been increasing since 1966 which led to
the renewed local transmission to a level that is currently higher than the imported
cases (24)
 In year 2000, a total of 763 cases of malaria were registered, 47 of which were
indigenous and included locally transmitted P. vivax in the Moscow area. (24)
 The incidence of indigenous malaria doubled between 1997 and 2001 necessitating
the implementation of an active vector programme. (Note: No cost figures for such an
implementation programme were found).
Newly Independent States (Azerbaijan, Tajikistan) and Turkey
Malaria resurgence is serious and constitutes a threat to those areas of Europe especially the
Balkans. Table 6
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6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
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
Most cases are due to P. vivax although there have been a number of P.falciparum
(Note: no data provided on mortality, morbidity or the cost of treatment)
Influx of refugees from malaria endemic area, the breakdown in health services, the lack of
vector control and failure to carry out surveillance and control measures contribute to the
resurgence of malaria in these countries.
Table 6: Autochthonous(Indigenous) malaria reported in eastern Europe (5)
1996
1997
1998
1999
Country
149
567
542
329
Armenia
13,135
9,911
5,175
2,311
Azerbaijan
3
0
14
15
Georgia
10
31
63
77
Russian Federation
16,561
29,794
19,351
13,493
Tajikistan
60,634
35,376
36,780
20,908
Turkey
3
4
115
10
Turkmenistan
2000
56
1,526
244
43
19,064
11,381
18
b) Imported Malaria
Imported malaria cases refer to acute malarial disease detected in travelers (tourists, military
personnel or business people) returning from malaria-endemic countries. Airport malaria
resulting from inadvertent transport of live infected mosquitoes aboard an aircraft arriving
from a malaria-endemic country is considered imported malaria although the transmission
of the parasite to human occurs locally. (5)
The WHO Regional Office for Europe reported a total of 15,528 cases of imported malaria in
the year 2000. (5) In the European Union, 10,000 to 12,000 cases are recorded each year (23/100,000 population) but the actual number may be as high as 20,000 per year if one
considers that a large number of cases are not diagnosed and/or reported (Table 7).
Table 7: Imported cases of malaria in Europe 1996-2000 (5)
Country
Austria
Belgium
Denmark
France
Germany
Italy
Netherlands
Norway
Russian Federation
Spain
Sweden
Switzerland
United Kingdom
1996
87
n/a
191
5,109
1,021
760
308
101
601
224
189
292
2,500
1997
1998
75
n/a
213
5,377
1,017
814
223
107
798
291
183
319
2,364
1 Preliminary data
6.10-13
80
334
174
5,9401
1,008
931
250
88
1,018
339
172
339
2,073
1999
93
369
207
6,1271
918
1,006
263
74
715
260
153
313
2,045
2000
62
337
202
8,0561
732
986
691
79
752
333
132
317
2,069
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
The number of imported cases has been increasing in all European countries over the period
1996-2000. Most of the cases are of P. falciparum and the most common area of origin is Africa.
In continental France and the United Kingdom, where the largest numbers are recorded,
imported malaria cases constitute both a serious public health problem and often grave
medical problems for the infected patients.
The overall burden of malaria cases (indigenous or imported) in Europe is not known.
However, based on available data and observations listed below, it appears that the risks
may be underestimated and that the lack of attention to the problem could result in a more
serious public health and economic burden in Europe.
Level of underreporting is estimated to be 20% in Finland, 55% in France and 59% in The
Netherlands. (25) (Note: No other country data was found on estimated underreporting.(26)

Within a decade (1989-1999) 680 people died of P. falciparum imported malaria cases in
the WHO European Region. Deaths often result from delayed diagnosis because
physicians are not often confronted with this disease and the increasing frequency of
drug-resistant strains among the imported cases.
Most countries where important surveillance data are available report that travelers’
compliance to prophylactic drugs or prevention measures are extremely poor due to
unpleasant side effects, complicated regimen and incorrect information provided by health
care professionals or tour operators.
In France, the overall cost of an uncomplicated case of malaria (medical expenses and an
average sick leave of two weeks) has been estimated at 6,400 Euros for inpatients and 1,400
Euros for outpatients.(27) Thus, for the more than 8,000 cases in the year 2000, the total cost to
the country could have been nearly 20 million Euros.
In Switzerland the average cost of the treatment of a single case of malaria was CHF
44,000.(28)
Control Strategy
In the 19th century, the distribution of malaria was widespread occurring not only in the
tropics, but in much of the temperate regions of the world, including parts of England,
Holland, central and southern Europe and in North Americas as far north as Montreal.(9,13)
The Global Eradication Campaign, which took place between 1955 and 1964 has clearly
restricted malaria distribution by eradicating it from North America and Europe. The
campaign largely relied on insecticides and drugs to wipe out the disease. Changes in
agricultural practices, improvement of lifestyle and quality of households as well as political
and social will and large funding commitments all contributed to its success in the
developed countries. However, the eradication campaign failed in the developing countries.
Today, it is generally accepted that eradication may not be a realistic goal in many parts of
the world. Nevertheless, controlling malaria and significantly reducing its burden on the
disease endemic countries are acknowledged as attainable goals, at least in the short to
medium term. (9,29)
6.10-14
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
The control of malaria is aimed at reducing mortality and disease incidence until it is no
longer a public health issue. It requires a good understanding of epidemiology by the
communities and health care providers. It also requires capacity strengthening of the health
care systems in many areas due to the spectrum of clinical manifestations of the disease from
mild cases in semi-immune individuals to severe life-threatening illness requiring
challenging medical management especially for children and pregnant women.
In 1952 Russell(30) proposed a classification of measures for the prevention and control of
malaria. Beales and Gilles published a comprehensive review of the principles driving
prevention and control, including those established earlier by Russell.(29)
For the purpose of this analysis, control strategies have been classified and summarized as
follows:



Vector control
Case management
Vaccine
Vector control aims at reducing the vector’s capacity to infect individuals by using personal
protection to block contact between humans and mosquitoes, diminishing the breeding
environment of mosquitoes and, using insecticide to reduce the mosquito population. Case
management includes the early diagnosis and treatment of infected persons. Vaccines may
offer protection but to date there is no malaria vaccine with proven efficacy.
Other important strategies are advocated by the WHO(31) and include: forecasting epidemic
outbreaks, development of epidemiological information systems, capacity building in basic
and applied research and ongoing assessment of ecological, social and economic
determinants of disease in affected regions.
Vector Control
Vector control has proven to be effective if employed adequately. The present discussion will
be limited to a brief description of the tools currently recommended and how they can
prevent human infection or transmission.(9,17,29)
1) Insecticide treated bed nets and other materials (ITN):
Bed nets and clothes impregnated with pyrethroid insecticides provide a chemical and
physical barrier between mosquitoes and individuals. They are useful in African settings
where the insects feed indoors during nighttime. In addition, insecticide helps reduce the
density of insects provided that the level of coverage and the use by the local population is
significant, thus limiting further transmission.
Pyrethroids are synthetic derivatives of pyrethrum, an extract of dried chrysanthemum
flowers, which act as nerve poisons that rapidly permeate and kill insects but show low
toxicity to mammals. The major limitation is the short-lived action, which results in the need
for re-treatment every 6 to 12 months. Long-lasting insecticide nets (i.e: with insecticide
incorporated directly in net fibers) would eliminate the need for frequent re-treatment. Early
6.10-15
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
prototypes introduced on the market gave unsatisfactory results but research and
development continues.
This method proved very successful in China and Vietnam, where governments promoted
the use of bed nets and also offered re-treatment free of charge. The WHO-Roll Back Malaria
strongly advocates the use of ITN and several programs are in place to provide large scale
coverage.(17) Personal protection has been shown to significantly reduce the risks of infection
but their use is highly dependent upon the level of education and family incomes.(11)
2) Indoor Residual Insecticide Spraying (IRS):
This method, consisting of spraying the inside surface of walls and ceilings of houses, was
introduced on a large scale in the 1930s, first, with pyrethrum and later with DDT. IRS works
by preventing a large proportion of mosquitoes from surviving 12 to 14 days, which is the
time it takes for the malaria parasite to develop to the infective stage within the mosquito. A
daily mosquito mortality rate of up to 40-50% can be achieved and, if used on a large scale,
can help reduce transmission in a community, even in non-users.(9-11) DDT-based IRS has
declined over the past 30 years, in part because of the development of DDT resistance in
vector and also because the general disapproval of DDT by the international community.
The International Convention of Persistent Organic Pollutants now contains an amendment
specifically excluding DDT for vector control from being banned. DDT-based IRS is
particularly appropriate in situation of epidemics as it was the case in Madagascar in the
1980's.(32)
3) Environmental and Biologic Management (source reduction):
This approach aims at preventing or reducing the breeding of mosquitoes or destroying the
larvae. This can be achieved by construction of dams, formation of reservoir and irrigation
systems, modifying the boundaries of rivers or their run-off systems, drying rice field
intermittently or other ecosystem modifying approaches. These methods can produce results
where the vector breeding sites are few in number and can be identified, such as in India and
in Southeast Asia.
The WHO has shown a renewed interest in environmental control of malaria vector and
issued two important publications on engineering and technical aspects of as well as
individual and community vector control:

Manual on environmental management for mosquito control, with special emphasis on malaria vectors .

WHO Offsets Publications, No.66 Geneva, Offsets Publications, 1982a
WHO Vector Control. Geneva, World Health Organization 1997b
Case Management
1) Diagnosis
The success of disease management relies on a prompt and accurate diagnosis, which is
based on confirmation of parasite in the blood. Young children may develop complications
6.10-16
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
of P. falciparum very rapidly and ideally treatment should be initiated within 12 hours of onset
of symptoms. Optimal diagnosis is made by microscopic examination requiring trained
laboratory technicians, well maintained equipment and reagents, all of which, is time
consuming and expensive. Because many health facilities in developing countries cannot
meet these requirements, diagnosis is based on clinical signs and symptoms, which include
chills, fever, diarrhea, general body aches or headaches. This clinical picture mimics that of
many other common diseases and in absence of a microscopic diagnosis treatment is
initiated on "presumptive" basis. Such practices result in 60% over-treatment and increases
costs significantly in addition to the potential health hazards associated to excessive drug
exposure and increased propensity for drug resistance.(17) This wastage could be reduced if
clinical diagnosis was done according to criteria based on epidemiology (transmission
season), age and gender of the patient.
Rapid diagnostic tests (RDTs), which are based on plasmodium antigen detection
incorporated onto a disposable dipstick and are easy to use by laypeople, have been
introduced recently. The test is sensitive but there is little information on its effectiveness
yet.(9) (See appendix 6.10.4)
2) Treatment of malaria cases
Malaria can be effectively treated with drugs. Currently, a number of antimalarials are
available, however, two of the most widely used drugs, chloroquine and SP are useless in
many parts of the world due to drug resistance. The most favored antimalarial on the
market for uncomplicated P. falciparum malaria is artemether-lumefantrine, a fixed-dose
artemisinin-based combination therapy (ACT) as recommended by the WHO for first line
treatment. (10)
The complexity of host response to this infection makes evaluation of drug efficacy difficult.
Furthermore, the plasmodia that have entered into the patient blood stream will undergo
asexual maturation and another round of multiplication or a number of parasites will have
transformed into sexual forms called gametocytes. Because each stage of the parasite lifecycle exhibits distinct biochemical characteristics, one drug may kill one stage of the parasite
but have little or no effect on another. Most drugs are inactive against gametocytes. In P.
falciparum, gametocytes emerge after 10 days and, once ingested by a mosquito after it has
bitten an infected human, can perpetuate transmission. Therefore, initiating treatment early
with an effective antimalarial drug can make a significant impact in the transmission rate, at
least for P. falciparum infection. Several antimalarial drugs are currently marketed in oral or
parenteral (injectable) formulation and to treat or prevent malaria (Table 8).
6.10-17
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
Table 8: Characteristics of currently available antimalarial drugs.
Drug name
Indication
Limitations
Quinine (QN)
cure
symptomatic
infection,
severe and cerebral malaria1
cure symptomatic infection, IPT2
compliance, resistance, safety
prophylaxis for travelers and
antirelapsing3 for P.vivax or P.
ovale;
transmission
blocker
(gametocytocidal)4
cure
symptomatic
infection,
prophylaxis for travelers and IPT
cure symptomatic infection
compliance, safety,
poor activity on blood schizonts
cure
symptomatic
infection,
severe and cerebral malaria,
(gametocytocidal)4
cure
symptomatic
infection,
prophylaxis
cure symptomatic infection
cost, length of treatment,
safety in early pregnancy?
Arthemeterlumefantrine
Chlorproguanil/
Dapsone (Lapdap™)
Proguanil/Atovaquone
(Malarone™)
cure symptomatic infection,
(gametocytocidal) 4
cure symptomatic infection
compliance, cost, resistance,
safety in early pregnancy
resistance, safety in G6PD deficiency,
safety in pregnancy
cost, resistance
Piperaquine/
Dehydroartemisinin
(Artekin™)
cure symptomatic infection
(gametocytocidal) 4
Chloroquine (CQ)
Primaquine
Sulphadoxine/
Pyrimethamine (SP)
Amodiaquine (AQ)
Artemisinins
Mefloquine
Halofantrine
cure symptomatic infection,
prophylaxis for travelers
resistance, safety at high dose
resistance
resistance, safety
resistance, cost, safety
resistance, safety, cost
potential resistance, availability of GMP
material, safety in pregnancy
1 Severe malaria: Outline classification of sever malaria is as follows (33):
Group 1: Children t immediate risk of dying who require parenteral antimalarial drugs and supportive therapy
(a) Prostrated children (prostration is the inability to sit upright in a child normally able to do so, or to drink in
the case of children too young to sit)
Three subgroups of increasing severity should be distinguished
i) Prostrate but fully conscious
ii) Prostrate with impaired consciousness but not in deep coma
iii) Coma (inability to localize a painful stimulus
(b) Respiratory distress
i) Mild-- sustained nasal flaring and/or mild intercostals indrawing (recession)
ii) Severe--the presence of either marked indrawing (recession) of the bony structure of the lower chest
wall or deep (acidotic) breathing
Group 2: Children who, though able to be treated with normal antimalarial drugs require supervised
management because of the risk of clinical deterioration but who show none of the features of group 1 (above)
(a) Children with a hemoglobin level < 5 g/dL or hematocrit < 15%
(b) Children with 2 or more convulsions within a 24 hour period
Group 3: Children who require parenteral treatment because of persistent vomiting but who lack any specific
clinical or laboratory features of groups 1 or 2 (above)
2 IPT= Intermittent preventive treatment: drugs administered intermittently to prevent malaria attack in
children or complications in pregnant women
3 Anti-relapsing: also referred to as radical cure because it kills the hypnozoites or latent liver stage
4 Gametocytocidal: sterilization of mature gametocytes but the effect on malaria transmission has not been
rigorously evaluated in clinical studies.
6.10-18
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
Results from controlled and uncontrolled clinical trials assessing efficacy of any given drugs
are sometimes conflicting but nevertheless it is widely recognized that prompt intervention
with an effective antimalarial reduces morbidity and mortality associated with malaria.(17)
The choice of drugs should depend on a variety of factors such as the pattern of resistance,
cost, safety (side-effects), pharmacokinetics, compliance (adherence to treatment regimen)
availability and access. The ideal drug for endemic countries should be one that meets all of
the following:








active against resistant strains,
inexpensive
safe to use in pregnancy
safe use in children
option of oral and parenteral formulation
pharmacokinetics (should remain in the body long enough to cure in three days i.e.:
no recrudescence for at least 28 days post-treatment)
gametocytocidal
active against exo-erythrocytic (liver) stage of plasmodia where P. vivax is endemic
No such drug exists currently. The situation today is simple but tragic: drugs that are
inexpensive no longer work because of widespread resistance and drugs that do work are
not affordable by the economic standards of disease-endemic countries.
Antimalarial drug resistance is a major challenge in malaria treatment. Resistance results
from gene mutation in the plasmodium and many factors are known to influence the spread
of drug resistance. These factors may be genetic (the degree of resistance conferred by a
given mutation) or may be linked to the pharmacokinetics (drug concentration profile) and
pattern of drug use (quality, availability, distribution) or the immune status of the immunity
profile of a community. It is generally accepted that today's widespread resistance to
chloroquine (CQ) and sulfadoxine/pyrimethamine (SP) is the result of mass administration
and long-term use of these drugs. Chloroquine resistance was first described in the late 50's
in S.E. Asia and then in the'70s in Africa and resistance to SP was reported within about 1
year of its introduction.(9) Both drugs have lost clinical effectiveness in Africa where
treatment failure rates have reached 80% for CQ in some regions as illustrated in Figures 2
and 3.(17)
Drugs with long elimination phase play a role in resistance development by acting as
selective filters, allowing resistant parasite to survive and multiply while the residual drug
levels suppress the sensitive parasites. For example, mefloquine and piperaquine have a
long elimination phase that could lead to significant selection pressure. Inadequate treatment
protocol (dose level administered or duration) or poor quality drug product on the market
has also been associated with the development of resistance.
Finally the immunity status of a population contributes to resistance selection as the drug
resistant mutants are more likely to emerge from infections involving a large numbers of
parasites, which most often occur in non-immune individuals such as children. Therefore,
children or non-immune individuals infected with a large numbers of parasites who receive
6.10-19
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
inadequate treatment, (either because of poor quality drug, lack of compliance, vomiting an
oral treatment, etc.) are another potential source of resistance.
In order to delay the development and spread of drug resistance, combination therapy has
been recommended by the WHO as well as by most malaria experts.(10) Combination
therapy consists in administering concomitantly two or more antimalarials, preferably
containing artemisinin or one of its derivatives such artesunate, dihydroartemisinin,
artemether or arteether (known as ACT or artemisinin-based combination therapy).
Artemisinin is derived from a Chinese plant, Artemisia annua, and has been used as an
antimalarial in China for over 2000 years. It is today the most potent antimalarial, killing
rapidly the biomass of parasites in the blood. However, because of its very short half-life,
the drug is eliminated rapidly leaving an opportunity for the residual parasites in the blood
or the liver to recrudesce. To be effective as monotherapy, artemisinin must be given at least
twice a day for 5 to 7 days. By combining artemisinin with a drug having a longer
elimination half-life and a different mechanism of action, the probability for selection of
resistant parasite is less and treatment course can be reduced to about 3 days, thus also
increasing adherence to treatment. Resistance to artemisinin has not yet been reported but
concerns are increasing because of the potential emergence of resistant parasites if it is used
massively as monotherapy. Monotherapies can also threaten the efficacy and resistance
potential of combination therapies.
6.10-20
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
Figure 2: Chloroquine Treatment failure in Africa (Source: Africa Malaria Report 2003 WHO 2003)
(17)
Figure 3: SP treatment failure in Africa (17)
The other important limitation of
artemisinin drugs is the cost. Because it is
derived from plant, several laborious
steps are necessary to finally develop the
end product. The crop must first be
planted and then harvested.
The
artemisinin must then be extracted,
purified, synthesized and then formulated
into a pill. Co-formulation (two or more
drugs in one pill) with the companion
drug(s) further adds to the cost of the final
finished product. The process takes a
total of 18 months, making quick scale-up
a challenge.
6.10-21
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
Table 9 lists the prices that Médecins Sans Frontières (MSF) pays for these drugs. The quality
standards (GMP status) may vary according to suppliers. Coartem, a co-formulation of
artemether and lumefantrine, recommended by the WHO, costs US$ 2.40 per treatment
course at wholesale and can be marked up to five times that amount in the private sector.
This price is not affordable by much of the population living in disease-endemic countries.
For some of the poorest people living with the disease, even a 10-cent dose of chloroquine is
already expensive. At US$ 0.10 per course, governments can afford or are able to find
external funding to buy chloroquine for the public sector needs. When multiplying the cost
of one treatment course with ACT by 200 to 400 million, the estimated number of treatment
courses required annually in Africa, it is not surprising that many African countries have not
yet switched to ACT drugs such as Coartem. In face of the burden that malaria represents
and because ACTs are not deemed affordable at present prices (between US$ 1.00 and 3.00)
many countries are changing malaria treatment policies and are buying non-fixed
combination of existing drugs such as CQ +SP or AQ plus SP or, if a little more fortunate,
they can afford CQ+ and artemisinin, SP + artemisinin or amodiaquine. Many of these nonfixed combinations have not been rigorously tested for safety or efficacy but they are used in
the interim, until affordable new drugs become available.
6.10-22
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
Table 9: Wholesale prices for Artesunate (semi-synthetic artemisinin derivative) (9)
Drug
Range of prices for standard adult dose
Artesunate
Asian suppliers:
US$0.50 (not yet in production); less for greater quantities
US$0.63; 15% discount for greater than 1 million
treatments
US$1.25 (not yet in production)
US$1.26; decreasing to US$1.01 at 3 million treatments
US$1.35
European suppliers:
US$2.68 (2.10 Euros)
US$2.42 (1.90 Euros)
African suppliers:
US$5.36
Coartem
US$2.40 for public services of developing countries (tiered
pricing; higher for all other buyers)
CV8 (8 tablets)
US$1.21 for <1 million treatments; US$0.97 for > 1 million
treatments
Artekin II
US$1.00 at retail
AS + AQ blister
Asian suppliers:
US$1.50 (not yet in production)
<US$1.91 (1.50 Euros) (not yet in production)
European suppliers:
US$1.53 (1.2 Euros)
US$1.91 (1.5 Euros)
US$2.68 (2.10 Euros) for<500,000 treatments; US$1.39 (1.09
Euros) for >500,000 treatments
AS + SP blister (6 tablets)
European suppliers:
US$2.42 (1.90 Euros) for <500,000 treatments; US$1.24
(0.97 Euros) for >
AQ = Amodiaquine
AS = Artesunate
SP = Sulfadoxine-Pyrimethamine
CV8 = a new combination of dihydroartemisinin, piperaquine, trimethoprim and primaquine
From:: J.M. Kindermans, Médecins Sans Frontières, 2003
Older antimalarials (Table 8) have not been submitted to the battery of safety pharmacology
and toxicology testing currently required by international regulatory standards. Almost no
post-marketing surveillance (PMS or pharmacovigilance) data have been generated
following introduction of CQ, SP or AQ. For newer drugs, safety data are largely derived
from studies to assess prophylactic efficacy of these drugs in non-immune travelers (for
6.10-23
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
example, mefloquine or atovaquone/proguanil). Therefore, the true toxicity of these drugs in
African populations is poorly understood and documented. Given the clinical experience
gained worldwide, most drugs are considered relatively safe when used under adequate
medical surveillance and control.
However, in endemic countries, self medication is
common place because health service infrastructure is nonexistent or inadequate. Most rural
populations, where malaria burden is higher, lack basic health care services. In addition,
many health facilities, where they exist, encounter difficulties keeping up with procurement
of essential drugs. This coupled with other challenges such as distance to the health care
facility are disincentives to the rural populations to call upon health systems for antimalarial
treatment. In Africa, between 70 % and 90% of febrile events in children are treated at home
in absence of medical diagnosis. Not all febrile events are due to malaria infection but yet
many children are exposed repeatedly to potentially toxic drugs. In absence of a reliable
health care infrastructure one can assume that pharmacovigilance is equally deficient and the
long-term effect of multiple drug exposure on growth and development of children is not
known. CQ, the most widely and frequently used drug throughout Africa seems to have the
least documented adverse drug reaction risk description. (12)
As mentioned above, the malaria burden is serious in pregnant women (Table 3). In addition
to the prompt treatment of a clinical manifestation, the WHO recommends that intermittent
preventive treatment (IPT), consisting of two full courses of treatment with an effective
antimalarial drug, be made available as part of antenatal care to women in their first or
second pregnancies in high transmission areas. (17) Due to the high prevalence of chloroquine
(CQ) resistance, sulfadoxine/ pyrimethamine (SP) is the only antimalarial available for use in
pregnant women. It has been shown to reduce severe anemia and largely eliminates low
birth weight. In addition it was more cost effective than CQ. An effective replacement
alternative to SP is needed because the efficacy of this drug is now compromised throughout
most of Africa. Other antimalarials are under study to determine whether they are safe and
effective for IPT. Recent surveys confirm that at least two-thirds of pregnant women attend
antenatal clinic in most African countries at least twice during pregnancy (from second
trimester), which provide an opportunity to deliver a prevention drug package. However,
visits to antenatal clinics do not necessarily translate into full coverage of IPT as it was
observed in Malawi where, a significant increase to 75% coverage was achieved after a well
coordinated education campaign about the benefit of IPT during antenatal clinic. (17)
IPT in infancy has also been shown to reduce severe anemia and deaths. In Tanzania, a
study showed that clinical malaria was reduced by 60% and severe anemia by 50% in
children who received two treatments of SP during their first year of life. (17) Additional
studies are underway to evaluate the efficacy and safety of IPT in infancy. However, there
are concerns that chemoprophylaxis provided at weekly or fortnightly intervals may be
difficult to sustain and where it is possible, it may accelerate the onset of resistance and
could impair the development of natural immunity.
Vaccines
Although vaccines have been one of the most cost effective and easily administered means of
controlling infectious diseases, safe and effective malaria vaccine are not yet available and
are not expected before another decade. (34)
6.10-24
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
The development of a malaria vaccine is challenging because the malaria parasites have
complex life cycles and thus, distinct development stages, each of which has multiple
antigens that could serve as targets of an immune response. The current approaches to
malaria vaccine development can be classified as follows. (35)
1) A pre-erythrocyte that would protect against the infectious form injected by the
mosquito (sporozoite) and/or inhibit the development in the liver.
2) An erythrocyte or asexual blood stage vaccine that would inhibit parasite
multiplication in the red cells, thus preventing (or decreasing) severe disease during the
blood infection.
3) A gametocyte or sexual stage vaccine that would interrupt the cycle of transmission by
inhibiting the further development of parasites ingested by the mosquito.
Much research is still needed to discover and develop a safe and effective vaccine but several
and studies indicate that it is an achievable goal. The rationale is based on the following
observations. (35)
Subjects living in malaria endemic regions naturally acquire protective immunity against
clinical disease
Inoculation with attenuated sporozoites can immunize patients against subsequent malaria
infection
 Immunoglobulin purified from the blood of immune individuals can passively
transfer protection against P. falciparum.
Early clinical trials of defined vaccines have shown some degree of efficacy.
Why does the disease burden persist? What can be learnt from past
and current research?
The reasons for the resurgence of malaria over the past few decades are complex and involve
the interplay of environmental, social and political factors.
Technical obstacles such as increasing resistance to insecticides and to drugs, greater
exposure to mosquito bites due to primitive housings contributed to the failure of achieving
or maintaining control of malaria. The continued problem of the lack of basic health care
poses huge challenges in case management of malarial. Further, regional wars, civil unrest,
extensive agricultural development projects have worsened the situation by forcing
migration of people into highly endemic areas where public health infrastructure is the
weakest. Trends in weather pattern such as global warming have been associated with the
increase of mosquito population in previously malaria-free areas and El Niño-induced floods
is thought to be responsible for local epidemics. Of all the factors cited, most experts agree
that the most important is the wide spread resistance to antimalarial drugs in disease
endemic areas.
In 1998 the WHO launched the Roll Back Malaria (RBM) initiative to spearhead the global
effort to control malaria by acting as a coordinating body in the fight against the disease.
6.10-25
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
The mandate is to half the malaria burden worldwide by 2010 by achieving the following
goals:




to provide 60% coverage of children and pregnant women with insecticide treated
bednets
to have 60% of malaria cases receive an effective treatment within 24 hours of the
onset of symptoms,
to ensure that 60% of pregnant women receive IPT
to enable detection of 60% epidemics within two weeks of onset and implement a
response within the next two weeks.
The Commission of Macroeconomics and Health has estimated that an immediate injection
of US$ 1 billion per annum was needed to work toward the goals of RBM. Despite
improvement in international support and donors expenditures over the past few years, the
pledges from donors to date are far below this target. However, even if this financial target
is achieved, the morbidity and mortality burden is unlikely to change if antimalarial drugs
continue failing due to resistance, poor compliance (effectiveness), safety or high cost.
Immediate replacement drugs for CQ and SP include amodiaquine and the fixed
combination of chlorproguanil/dapsone (Lapdap ®). However, these drugs already suffer
from some cross-resistance with CQ and SP thus, shortening their therapeutic life time and
their safety has not yet been fully established in areas where no pharmacovigilance exist.
The combination of expensive semi-synthetic artemisinins with older drugs is a short to
mid-term solution. SP, the only antimalarial recommended for pregnant women, suffers
from widespread resistance. Providing IPT to 60% of pregnant women with a failing drug is
not going to change the picture of anemia and low birth weight. Primaquine introduced in
the 1940's is still the only existing drug for radical cure (anti-relapse) of vivax malaria.
Clearly, new drugs are needed and strategies directed to the discovery and development of
safe, effective and affordable drugs must be implemented urgently.
Drug R&D is challenging, requiring scientific and technical skills, and enormous capital.
The research-based pharmaceutical industries spend on average US$ 800 million for every
new drug when taking into account the high R&D failure rate. The return on investments
must be high to justify such spending. Unlike diseases affecting populations of Europe,
North America and Japan for which the market system has produced innovative therapies,
tropical diseases in developing countries, even considering the millions of sufferers, do not
generate the revenue to attract R&D investment for the pharmaceutical industry. In other
words, developing countries cannot pay for market-financed innovative therapies. As a
result, only 1% of 1,393 new chemical entities (NCE) were approved for tropical diseases
over the past 25 years with only four antimalarials registered between 1975 and 1999. (36)
Furthermore, these drugs were developed as prophylaxis for travelers or military personnel
and therefore are not appropriate and affordable by the population in the disease-endemic
areas. Currently most favored ACT are too expensive. Lower prices for ACT may be
expected as large-scale demand increases and induces competition among manufacturers.
That is also assuming that supply of the drugs can meet such demand, if not, the short term
scenario could actually mean that the prices may even increase. Higher demand may also
encourage the criminal exploitation of the sick and desperate people by peddlers or less
6.10-26
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
ethical manufacturers of counterfeit or poor quality drugs.
patients, it also jeopardizes the use of the registered drugs.
(9)
This not only endangers
The establishment of the Global Funds to Fight AIDS, Tuberculosis and Malaria as a
purchasing fund for procurement of antimalarials may, to some extent, provide a
mechanism to justify efforts in R&D. However, the fund is not intended to finance R&D
itself.
The discovery and development of the antimalarial drugs registered between 1975 and 1996
was funded largely by the public sector, in particular the military. The creation of the
United Nations Development Programme/World Bank/World Health Organization/ Special
Programme for Research and Training in Tropical Diseases (WHO/TDR) in 1975 facilitated
the establishment of a partnership approach to drug discovery and development between
public sector organizations and companies for those diseases lacking the market incentive.
Mefloquine and halofantrine were discovered, developed and registered as a result of
collaboration between the Walter Reed US Army Institute of Research (WRAIR), WHO/TDR
and the private pharmaceutical companies.(37)
This approach evolved rapidly and led to the creation of organizations such as the
Medicines for Malaria Venture (MMV, http://www.mmv.org), a not-for-profit organization
using a public-private partnerships (PPP) approach to discover, develop, and deliver new
antimalarials as "global public goods". This was made possible by recent increase in funding
opportunities through national governments, philanthropic organizations or private
industry. The establishment of the Bill & Melinda Gates Foundation with its mission of
supporting such innovative approaches for product development for neglected diseases has
made a tremendous impact in the capabilities of these PPPs.
To date sixteen PPPs have been established specifically for product development (PD-PPP)
in diseases otherwise neglected by the private sector. Like MMV, these PPPs use the private
sector approaches to face research and development challenges, and use the portfolio
management approach to pursue their goal of fulfilling a public health rather than
commercial need by developing a product specifically for use in developing countries.
These sixteen PPP represent more than 1.1 billion in committed funding which includes
funding received as well as funding that is pledged in the future. Structure, focus, size and
management of these PD-PPP have been subject of an in-depth review: Public-Private
Partnerships for Neglected Diseases Opportunities to Address Pharmaceutical Gaps for Neglected Diseases
(Chapter 8.1).
The large pharmaceutical companies are also increasingly becoming involved in the search
of new therapeutic tools for neglected diseases, which facilitates the establishment of drug
development partnerships. For instances, GSK has established Diseases of the Developing
World Initiative; Sanofi has established Malaria Impact Initiative and Novartis has
established the Novartis Institute for Tropical Diseases. Pfizer is currently sponsoring
clinical trials to assess the safety and efficacy of the combination of azithromycin and
chloroquine for uncomplicated malaria.
6.10-27
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
In only four years of operation MMV is managing the largest-ever portfolio of malaria drug
research, with 21 projects which will be discussed in further details below. More important
than the total number of projects, is the fact that the portfolio includes eight completely new
classes of drugs, illustrating the opportunity for innovation that PPPs has to offer. Such
advances result from MMV's collaborations with 40 public and private institutions around
the world. Partnerships operate within a well established contractual framework:
pharmaceutical, biotec and research institute partners contribute their know-how, staff,
infrastructure and facilities to individual projects, while MMV and its Expert Scientific
Advisory Committee manage the portfolio as a whole.
There is much hope that efforts resulting from innovative-discovery will continue to feed the
antimalarial pipeline as exciting scientific breakthroughs have occurred in our knowledge of
the biology, immunology and molecular genetics of malaria. The P. falciparum genomic
information can be exploited to yield new therapeutic targets, as well as antigens for
potential vaccines. The potential offered by the improved understanding of the biochemistry
pathways of the plasmodia is illustrated in Table 10 below. A comprehensive review of
recent advances in target selection and validation and, screening methods of antimalarial
drug candidate has been published recently by Fidock et al. (38)
These innovation opportunities need not only to be seized but also transitioned into a malaria
specific drug development program to ensure that the new drug candidates translate into
treatments fulfilling the ongoing unmet medical needs in malaria.
6.10-28
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
Table 10: Targets for antimalarial chemotherapy (Source: Fidock et al, 2004) (38)
Reproduced with permission from Nature Reviews (www.nature.com/reviews) Drug Discovery
(Vol 3, No. 6, pp 509-520)copyright (2004) Macmillan Magazines Ltd.
Target location
Cytosol
Pathway/mechanis
m
Folate metabolism
Glycolisis
Protein synthesis
Glutathione
metabolism
Signal transduction
Unknown
Parasite
Membrane
Food vacuole
Mitochondrion
Apicoplast
Extracellular
Phospholipid
synthesis
Membrane
transport
Haem
polymerization
Haemoglobin
hydrolysis
Free-radical
generation
Electron transport
Protein synthesis
DNA synthesis
Transcription
Type II fatty acid
biosynthesis
Isoprenoid
synthesis
Protein
farnesylation
Erythrocyte
invasion
Target molecule
Examples of therapies
Dihydrofolate
reductase
Dihydropteroate
synthase
Thymiclylate synthase
Lactate
dehydrogenase
Peptide deformylase
Heat-shock protein 90
Glutathione reductase
Protein Kinases
Ca2+ - ATPase
Choline transporter
Unique channels
Hexose transporter
References
Existing therapies
New compounds
Pyrimathamine,
proguanil
Sulphadoxine,
dapsone
Chlorproguanil
82,83
5-fluorootate
Gossypol
derivatives
Actinonin
Geldanamycin
Enzyme
inhibitors
Oxindole
derivatives
84
85
86
87
88
89
90
G25
71
Dinucleoside
dimmers
Hexos
derrivatives
New quinolines
Protease
inhibitors
Protease
inhibitors
New peroxides
91
Artemisinins
Quinolines
92
Haemozoin
Plasmepsins
Falcipains
Unknown
Chloroquine
Cytochrome
c
xidoreductase
Apicoplast ribosome
DNA gyrase
RNA polymerase
FabH
FabI/PIENR
DOXP
reductoisomerase
Farnesyl transferase
Atovaquone
101
Tetracycline,
clindamycin
Quinolones
Rifampin
102
Subtilisin
proteases
Artemisinins
serine
Thiolactomycin
Triclosan
Fosmidomycin
Peptidomimetics
29
32,33,103
30
25,104
Protease
inhibitors
97,105
DOXP, 1-deoxy-p-zylulose 5-phosphate; PIENR, Plasmodium falciparum enoyl-ACP reductase
6.10-29
93,94
95,96
97,98
99,100
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
What is the current pipeline?
For the purpose of this analysis, projects have been classified under two main categories:
 Development: includes all projects for which compound has been selected for full
scale regulatory pre-clinical or clinical development programme.
 Discovery: includes all projects for which compound has not yet been selected
Development Projects
Drug name(s)
Sponsoring Organizations
Rectal artesunate
ChloroquineAzythromycin
Status
WHO/TDR
Pfizer
Pre-registration
Phase II/III
Artemether-lumefantrine
Pediatric Coartem
MMV- Novartis-(WHO-TDR)
Chlorproguanil-dapsoneArtesunate (ACT)
MMV- GSK- WHO/TDR,
Line extension
Phase II
Improved pentamidine
DB289
MMV- Immtech International
Univ. North Carolina
Phase II
MefloquineArtesunate (co-package)
DNDi, TROPIVAL (France),
Far Manginhos, Brazil
Phase I/II
AmodiaquineArtesunate (co-package)
DNDi, TROPIVAL (France)
Far Manginhos, Brazil
Phase I/II
Synthetic Peroxide
OZ277/RBX11160
MMV- Ranbaxy (India)
Phase I/II
Pyronaridine-artesunate
MMV- Shin Poong Ltd. (Korea)
Phase I/II
Intravenous artesunate
MMV- WRAIR (USA)
IND
Dihydroartemisinin
piperaquine (Artekin)
MMV- Holleykin (China)
Sigma-Tau (Italy), Oxford University
Pre-clinical GLP
Clinical GCP
Artemifone
MMV- Bayer (Germany)
Phase I/II
8-aminoquinoline
NPC1161B
MMV- Univ. Mississippi
Pre-IND
4-aminoquinoline
Isoquine
MMV- GSK- Univ. Liverpool (UK)
Transition
4-aminoquinoline AQ-13
Tulane Univesity- NIH
CQ-Methylene Blue
NIH
MSD-Univ. Heidelberg
6.10-30
Phase II
Phase II
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
Discovery Projects
Project name(s)
Sponsoring Organizations
Status
Dicationic molecules
MMV- Univ. North Carolina
Georgia State Univ.
Swiss Tropical Institute
4 (1H)-pyridones
MMV-GSK (Spain)
Pre-clinical
Novel tetracyclines
MMV-Paratek (USA)
Lead identification
Protein farnesylTransferase (Pf-PFT)
MMV-Univ. WashingtonYale University
Lead optimization
Manzamine alkaloids
MMV-Univ. MississippiUniv. MarylandGadjah Mada Univ. (Indonesia)
Lead optimization
Dihydrofolate reductase
MMV-Biotec (Thailand)London School of Hygiene and
Tropical Medicine (UK)Monash University (Australia)
Lead identification
Falcipain
MMV-Univ. San FranciscoGSK (Spain)
Fatty acid biosynthesis (FAS II)
MMV-Texas A&M-Albert Einstein
Jacobus Pharma
Lead identification
Glycerhaldehyde-3Phosphate dehydrogenase
(GAPDH)
MMV-Swiss Tropical Ins,Hoffman-LaRoche
Exploratory
Fatty acid
Biosynthesis (FAB I)
MMV-GSK (Spain)
Exploratory
Peptide deformylase
MMV-GSK (Spain)
Exploratory
Lead optimization
Lead identification
In addition to this portfolio, one should mention the significant efforts of research and
development deployed by the Walter Reed Army Research Institute of Research (WRAIR),
through the United States Army Medical Research and Material Command (USAMRMC) in
the search of new antimalarials. (9) Several families of compounds in various stages of preclinical development include:






Pyrroloquinazolines
3rd generation antifolates
Imidazolinedione derivatives
Tryptanthrins
New macrolides and ketolides
Chalcones
6.10-31
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting



Methylene Blue
Mefloquine analogs
Tafenoquine
Many of these compounds were selected on the basis of their prophylactic potential as they
are intended for soldiers on mission in malaria endemic countries. The desired drug profile
needed to treat uncomplicated or severe malaria in developing countries is very specific to
these populations and will be discussed in further detail below.
For the non-initiated to the complexity and risk associated with innovative drug discovery
and development, the current antimalarial portfolio may appear like a Roman feast and thus,
one could question the rationale for the quest of new drugs. While the innovation is
paramount this does not simply mean new drugs. The challenge is not so much about
developing newer drugs but developing better drugs, those that will be custom-made for the
most neglected, namely children and pregnant women. In addition, it is not expected that
these projects will all succeed. R&D is high-risk, with more failures than successes. Hence, a
sustainable pipeline of drug research is necessary in order to yield effective, affordable and
appropriate antimalarials.
Given the devastating impact of multi-drug resistance, delivering artemisinin-fixed
combination therapies in the immediate future is a priority in line with the WHO-RBM's
objectives. This is why the portfolio includes many new ACT or new formulations of existing
drugs, such as: pediatric formulation of Coartem (lumefantrine- artemether) and rectal and
intravenous formulations of artesunate. Likewise the following fixed and non-fixed ACT
may be viewed as the low hanging fruits as they are combinations of older drugs with
known safety and efficacy profiles. All are currently in various phases of clinical trials and
for the most advanced products, approval of a marketing application by at least one
internationally recognized regulatory authority is contemplated as early as 2006 or 2007.
Their success will depend not only on the evidence of safety and efficacy but also stability
(shelf-life), availability (access) and cost.





artesunate with chlorproguanil-dapsone (CDA),
mefloqine-artesunate (non-fixed)
amodiaquine-artesunae (non-fixed)
artesunate: pyronaridine
DHA:piperaquine (Artekin)
DB289, an improved pentamidine-like molecule showed good activity in a proof of concept
study and is now undergoing further biopharmaceutical studies to determine whether the
total daily dose can be increased in order to shorten the treatment course to 3 days. There is
much hope that the synthetic peroxide (OZ277/RBX11160) will provide an alternative to the
costly semi-synthetic artemisinin derivatives. A large phase I study is currently taking place
in the UK and data to date justify progression to a proof of concept in malaria patients within
the next few months. In line with current WHO recommendations discouraging the use of
drug in monotherapy for the treatment of acute uncomplicated malaria, these drugs, as well
as all other new drugs in MMV's portfolio, will be developed as fixed dose combination
therapy unless there is a strong rationale or new recommendations arguing against this
6.10-32
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
approach. There are currently two exceptions: rectal and intravenous formulations of
artesunate, which are intended for severe malaria in situations where drugs cannot be
administered orally and a drop of the parasite biomass must be achieved rapidly and can be
followed with a definitive therapy.
There are a number of additional challenges to developing fixed-dose combination.
Additional pre-clinical studies are required to preclude antagonistic effects, or safety
concerns. This means further pharmacology and toxicology studies prior to progressing to
clinical trials. Pharmaceutical development may be challenged by chemical incompatibility.
Safety and efficacy trials must be preceded by well thought drug-interaction and dosefinding studies.
Significant funding will be required to bring these ACT and other new drugs on the market.
MMV estimates that US$ 30 to 50 million will be needed annually to bring its products to
registration. The newly established European Developing Countries Clinical Trials
Partnership (EDCTP), committed to building clinical research capacity in developing
countries, may bring significant support to MMV. Indeed, it is hoped that funding from
EDCTP will be used to develop clinical trial site infrastructure and resources necessary to
conduct research to international standards. Developing this capacity in developing
countries is an absolute prerequisite to MMV’s success in conducting phase II-III studies to
GCP standard acceptable by the competent regulatory authorities worldwide. However, for
continued justification of EDCTP's existence, one must ensure that there are sufficient new
chemical entities to be tested.
Opportunities for research and what are the gaps between current
research and potential research issues
In a recent communication, Lester M. Crawford, Acting Food and Drug Administration
(FDA) Commissioner noted that while historically 14% of drugs that entered phase I clinical
trial eventually obtained approval, now 8% of these drugs make it to the market. Filings of
standard new molecular entities have also fallen by over 50% in less than 10 years, going
from 34 in 1995 to 12 in 2003. This has pushed the cost of developing a single drug from
US$1.1 billion in 1995 to 1.7 billion in 1997.(39) The reasons for the growing attrition rate are
not clear but they certainly include the increasing complexity of the regulatory requirements
as well as the several changes occurring in the pharmaceutical industry businesses. In
response to the growing cost and complexity of drug development the FDA launched a
program called Critical Paths to investigate strategies for improving the drug development
process to reduce attrition.(39)
Drug candidates fail to achieve registration for several reasons in addition to those that are
purely business decision. Toxicity is responsible for 21 % of failures, lack of activity or
efficacy accounts for 29 % and oral bioavailability and formulation issues are responsible for
39 %. The steps that occur between discovery of a biological target and a drug candidate for
development are crucial, requiring a multidisciplinary approach from medicinal chemistry,
pharmacology, toxicology, pharmacokinetics as it was illustrated in a comprehensive review
by Nwaka and Ridley.(37)
6.10-33
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
To optimize the drug selection process, MMV has defined a target product profile as follows:







Efficacy against drug resistant strains
Cure within three days (once a day dosing regimen)
Low propensity to generate rapid resistance
Safe in small children (< 6 mos.)
Safe in pregnancy
Appropriate formulations and packaging
Low cost of goods
Drugs are also evaluated based on their potential to be used for the following indications:





Intermittent treatment in pregnancy and infancy
Treatments suitable for emergency situations e.g. single dose treatment for refugee
camps
P. vivax malaria (including radical cure)
Severe malaria
Prophylaxis
To reach this goal, the drug discovery process must rely on a prospective multidimensional
lead optimization integrating antimalarial, physicochemical, metabolism, pharmacokinetic
and toxicity. For instance, OZ277/RBX11160 was selected using a "selection matrix" based on
the target characteristics and yield a compound with several advantages over those of semisynthetic artemisinins.(40,41) Progression of OZ277 to development candidate took
approximately three years and the compound is currently in phase I study, which is an
encouraging result for the partnership approach (http://www.mmv.org).
However it is not known at this time whether this product or other products at this stage of
development will be safe in small children or pregnant women as there is no predictive
model that can be included in the "selection matrix" package.
Artemisinin derivatives have been taxed for a long period of time with neurotoxicological
safety concerns based on animal studies. Many thousands of patients, adults and children,
have taken these drugs over the past few decades and today there is no serious evidence of
neurotoxic effects. They are generally considered safe except in the first trimester of
pregnancy. This is again based on animal studies that showed fetal resorption, fetotoxicity
and possibly teratogenicity under very specific conditions.(42) Whilst there is nothing to
suggest this is true for humans, the drug is not recommended for use in early pregnancy and,
current advice is that artemisinin containing drugs should only be used in later pregnancy
when there is no other treatment available. There is limited safety data in pregnant women
based on relatively small studies done in Southeast Asia and trials are in progress in African
women in their second and their trimester of pregnancy. Trials during first trimester would
be considered unethical and no sponsors would assume such a liability risk even though no
one really knows the risk. It will take a very long time to find out if artemisinins cause
harmful effects to fetus or women during the first few days/weeks of pregnancy. It is the
clinical experience from women treated with artemisinin and who are unaware of their
pregnancy that will determine whether it is safe or not. With the tools that are available to
6.10-34
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
scientists today, there should exist a better way to predict drug safety in pregnancy. For
antimalarials as it is the case for most drugs, a definitive assessment of risk for use during
pregnancy (fertility outcomes, effect on labor and delivery, fetal development, birth defects
and other fetal toxicities) is not available at the time of product approval.
The same issues apply to safety in children and infant. Recent regulations make it not only
possible, but mandatory, to involve children in clinical trials of investigational drugs, and
draft guidelines on juvenile toxicity studies have been issued to make this possible. The
limitations of animal data in reproductive toxicology studies hold true for the juvenile
animal studies. Furthermore, these studies rely on cumbersome, costly assessment methods
with no assurance that they will be predictive of potential adverse outcomes in humans.
There are not yet adequate, cost-efficient, pre-clinical study models that can be used in a
drug selection matrix to determine whether a drug can be safe in pregnancy or small
children. These assessments can only be done during late stage development. Given that
malaria is most devastating in these populations, it is imperative that pharmaceutical
industries, regulators and academic scientists work on the development and validation of
new experimental methods to evaluate product safety earlier in the development process.
Research directed toward improving a drug development toolkit, containing methods using
animal, cells-culture, biomarkers and computer-based predictive models to screen drug
candidates for safety is warranted to meet increasing challenge of drug development.
Conclusions and Recommendations
□ P. falciparum malaria kills over one million people and causes up to 500 million cases
annually, affecting mainly young children and pregnant women. Vivax malaria is responsible
for 70-80 million cases per year accounting for 50% of all malaria cases, mostly outside
Africa.
□ The economic consequences are enormous in Africa, with an estimated US$ 12 billion per
year in lost GDP and a loss of 45 million years of productive life due to deaths and disability.
Households spend up to 30% of their income on malaria related expenses.
□ The number of imported malaria cases is increasing Europe and deaths occur due to a lack
of recognition of the disease and sometimes because of poor medical management.
□ There is no safe and effective vaccine to date and those currently in development are not
expected to provide long-term nor complete protection.
□ Malaria is curable and preventable. The principal control strategies include case
management by rapid diagnosis and effective treatment and, personal protection with bed
nets.
□ Effective drugs exist. Drugs such as CQ and SP and have proven to be useful in the control
of malaria but wide spread resistance make these drugs useless in much of the diseaseendemic areas. Newer artemisinin-based combination therapies are effective but are too
expensive for the people and governments in developing countries. CQ costs approximately
6.10-35
6.10 Analysis of Pharmaceutical Development Issues for Malaria as Basis
for Priority-Setting
US$ 0.10 per course while ACT cost 10 to 20 times more. New affordable, safe and effective
drugs are urgently needed to roll back malaria.
□ Adequate coverage of mosquito bed nets have been shown to reduce child deaths by 20%.
However they are not yet widely used due to cost and lack and the difficulty to sustain an
adequate coverage.
□ At least US$ 1 billion is needed annually to implement these control strategies. Pledges
from donors and government organizations are far below this target.
□ Today, it costs nearly US$ 800 million to discover and develop new drugs due to the high
attrition rate and stringent regulatory requirements.
□ The pharmaceutical industry has largely been disengaged from innovative drug R&D in
tropical diseases due to the lack of market incentive.
□ In the meantime, basic science made important advances in areas such as genetic and
molecular biology allowing better understanding of the parasite biology and identification of
drug target.
□ Innovation in basic science has not translated into new drugs because a funding gap exists
between basic science and research geared toward discovery and development of new drugs.
□ The creation of Public-Private-Partnerships (PPP) such as the Medicines for Malaria
Venture (MMV) provide a new cost-effective approach to innovative drug discovery and
development. In a few years of operation, MMV has built the largest-ever antimalarial
portfolio with a total expenditure of about US$60 million. Expenditures will increase
significantly as the drugs reach clinical trial phases. Collaboration with the EDCTP may help
support the cost of clinical studies (phase II-III studies) and thus facilitate rapid registration.
□ MMV estimates that at least US$ 30 to 50 million will be required annually to maintain a
sustainable portfolio in which new and better drugs can be developed that are appropriate
for people living in the disease-endemic areas.
□ Academic scientists, industry and regulators need to team up to translate the innovation
from basic research into applied sciences which will lead to the development of more cost
efficient experimental models for drug discovery and development. Increased funding of
innovative approaches toward applied sciences for drug R&D is an obligatory prerequisite
for the development of new medicines that will meet the global public health needs.
6.10-36
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for Priority-Setting
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