The Malaria Product Pipeline

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THE MALARIA PRODUCT PIPELINE: PLANNING FOR THE FUTURE

THE MALARIA PRODUCT PIPELINE:
PLANNING FOR THE FUTURE
THE GEORGE INSTITUTE FOR INTERNATIONAL HEALTH
Dr Mary Moran
Dr Javier Guzman
Anne-Laure Ropars
Dr Margaret Jorgensen
Alina McDonald
Dr Sarah Potter
Hiwot Haile Selassie
HEALTH POLICY DIVISION, THE GEORGE INSTITUTE FOR INTERNATIONAL HEALTH SEPTEMBER 2007
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HEALTH POLICY DIVISION

THE GEORGE INSTITUTE FOR
INTERNATIONAL HEALTH
Australia
Level 24, Maritime Trade Towers
207 Kent Street
Sydney NSW 2000
Australia
United Kingdom
Centre for International Development
36-38 Gordon Square
London WC1H 0PD
United Kingdom
Email: jguzman@george.org.au
aropars@george.org.au
mmoran@george.org.au
FOR FURTHER COPIES PLEASE CONTACT:

The George Institute for International Health
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Published by The George Institute for International Health
September 2007
This report was prepared by the Health Policy Division at The George
Institute for International Health through a project supported by the
Global Forum for Health Research through contributions from the World
Bank. The views expressed are those of the authors.
The George Institute for International Health is an internationally recog-

nised health research body. The Institute is affiliated with The University of
Sydney (NSW, Australia) and collaborates with other research institutes,
clinical authorities and policy centres around the world. The George
Institute has branches in Sydney, Beijing, Hyderabad and London.
Malaria Report facing pages 11 26/8/07 11:46 AM Page 1
> THE MALARIA PRODUCT

PIPELINE: PLANNING
FOR THE FUTURE
HEALTH POLICY DIVISION

THE GEORGE INSTITUTE FOR INTERNATIONAL HEALTH
Dr Mary Moran
Dr Javier Guzman
Anne-Laure Ropars
Dr Margaret Jorgensen
Alina McDonald
Dr Sarah Potter
Hiwot Haile Selassie
SEPTEMBER 2007
PAGE
CONTENTS
TABLE OF CONTENTS 3
ACKNOWLEDGEMENTS 4
ACRONYMS 5
EXECUTIVE SUMMARY 6
PREFACE 12
BACKGROUND TO CLINICAL DEVELOPMENT 13
SECTION 1. THE CURRENT AND FUTURE MALARIA PRODUCT PORTFOLIO 15
1.1 MALARIA VACCINES 15
1.2 MALARIA DRUGS 26
SECTION 2. RESOURCE IMPLICATIONS 33
2.1 DEVELOPMENT COSTS 33
2.2 MANUFACTURING DEMAND 37
2.3 TRIAL SITE DEMAND AND SUPPLY 39
SECTION 3. MANAGING THE TRIAL SITE NETWORK 51
3.1 WHERE WE ARE TODAY 51
3.2 CHALLENGE ONE: MATURING AND SUSTAINING YOUNG AND NEW LICENSURE SITES 51
3.3 CHALLENGE TWO: MAXIMISING SYNERGIES BETWEEN SITES AND TRIALS 56
SECTION 4. VACCINE POLICY PRICE-TAGS 59
4.1 SCENARIOS 59
SECTION 5. RECOMMENDATIONS 63
5.1 FUND MALARIA PRODUCT DEVELOPMENT 63
5.2 CONSOLIDATE THE CLINICAL TRIAL NETWORK 64
5.3 BUILD ON THE MALARIA VACCINE TECHNOLOGY ROADMAP 68
ANNEXES 71
REFERENCES 87
GLOSSARY 88
AUTHORS 91
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ACKNOWLEDGEMENTS
We would like to thank the many people who gave their time and expertise in the
course of discussions and consultations contributing to this project. The final report
could not have been prepared without the valuable input received from a wide range
of constituencies including experts in malaria product development, trial site directors,
and staff at numerous Product Development Partnerships, pharmaceutical companies,
biotechnology firms and public institutions. The report has benefited greatly from their
involvement, feedback and comments.
We particularly thank Simone Ghislandi, from the Department of Economics, University

of Oxford and Andrew Farlow from the Saïd Business School, University of Oxford, who
helped to develop the model used for our portfolio projections. The George Institute for
International Health is grateful for the support of the Global Forum for Health Research
through contributions from the World Bank.
PAGE
ACRONYMS
ACT Artemisinin Combination Therapy IRB Institutional Review Board

ADCI Antibody - Dependent Cellular Inhibition KATH Komfo Anokye Teaching Hospital - Ghana
AIA Afro-Immunoassay Network KCCR Kumasi Centre for Collaborative Research - Ghana
AIDS Acquired Immune Deficiency Syndrome KEMRI Kenya Medical Research Institute - Kenya
AMANET African Malaria Network Trust KHRC Kintampo Health Research Centre - Ghana
API Active Pharmaceutical Ingredient LSHTM London School of Hygiene & Tropical Medicine
AVAREF AFRO Vaccine Regulators Forum MCTA Malaria Clinical Trial Alliance
BMP Blantyre Malaria Project - Malawi MIAM Malaria Institute at Macha - Zambia
CDC U.S. Centers for Disease Control and Prevention MIP Malaria in Pregnancy
CDP Clinical Development Plan MLW Malawi - Liverpool - Wellcome Trust Research
CISM Centro de Investigação em Saúde da Programme
Manhiça - Mozambique MMV Medicines for Malaria Venture
CNRFP Centre National de Recherche et de MRC Medical Research Council - The Gambia
Formation sur le Paludisme - Burkina Faso MRL Malaria Research Laboratory - Nigeria
CRO Contract Research Organisation MRTC Malaria Research and Training Centre - Mali
CRSN Centre de Recherche en Santé de MSL Malaria Serology Laboratory
Nouna - Burkina Faso MVDB Malaria Vaccine Development Branch
CTC Clinical Trial Centre MVI Malaria Vaccine Initiative
CTF Clinical Trial Facility NCE New Chemical Entity
CVD Center for Vaccine Development NEPAD The New Partnership for Africa’s Development
DANIDA Danish International Development Agency NIAID National Institute of Allergy and Infectious
DMID Division of Microbiology and Infectious Diseases Diseases
DNDi Drugs for Neglected Diseases Initiative NIH National Institutes of Health
DSS Demographic Surveillance System NIMR National Institute for Medical Research - Tanzania
EDCTP European and Developing Countries Clinical NMRC Naval Medical Research Center
Trials Partnership PATH Program for Appropriate Technology in Health
EMVI European Malaria Vaccine Initiative PCR Polymerase Chain Reaction
EURHAVAC European Network for Harmonisation of PDP Product Development Partnership
Malaria Vaccine Development
PI Principal Investigator
FDA U.S. Food and Drug Administration
R&D Research and Development
FDC Fixed Dose Combination
SME Small to Medium Enterprise
GCP Good Clinical Practice
SMS School of Medical Sciences - Ghana
GIA Growth Inhibition Assay
SOP Standard Operating Procedure
GLP Good Laboratory Practice
TB Tuberculosis
GMP Good Manufacturing Practice
TDRC Tropical Diseases Research Centre - Zambia
GSK GlaxoSmithKline
UNICEF United Nations International Children’s
GSK Bio GlaxoSmithKline Biologicals Emergency Fund
HAS Hospital Albert Schweitzer - Gabon USAID United States Agency for International
HIV Human Immunodeficiency Virus Development
ICH International Conference on Harmonisation USAMRU-K U.S. Army Medical Research Project - Kenya
of Technical Requirements for the Registration WHO World Health Organisation
of Pharmaceuticals for Human Use
WHO/IVR WHO Initiative for Vaccine Research
IND Investigational New Drug
WHO/TDR UNICEF - UNDP - World Bank - WHO Special
IPTi Intermittent Preventative Treatment in infants Programme for Research and Training in
IPTp Intermittent Preventative Treatment in Tropical Diseases
pregnant women WRAIR Walter Reed Army Institute of Research
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EXECUTIVE SUMMARY
This report summarises our findings in a study of clinical development of malaria products
supported by the Global Forum for Health Research through contributions from the World
Bank. Our aim was to quantify the resources needed for clinical development of the global
malaria drug and vaccine portfolio over the five years to 2012, including funding
for clinical trials and associated manufacturing and toxicology, and demand for malaria
licensure trial sites. We also sought to provide policy-makers and funders with an analysis
of how these resources might best be allocated to advance the global malaria product
portfolio. Our brief included vaccine products for P. falciparum in Africa and drug products
targeted at both P. falciparum and P. vivax. Although our findings and recommendations
are our own, we acknowledge the extensive input of others, not least their patience in
providing us with insights into their projects and thinking.
SECTION ONE: THE CURRENT AND FUTURE candidates (45%) based on antigens discovered in the last
MALARIA PRODUCT PORTFOLIO 10-15 years
Lack of technical and policy tools to single out the best
The vaccine portfolio
vaccine candidates.
At first sight, today’s global malaria vaccine portfolio looks
Key factors reducing the number of malaria vaccines in
promising with 47 new vaccine candidates: 31 in preclinical
clinical trials include:
development, narrowing down to 16 in clinical trials. One of
these, the RTS,S vaccine being developed by GSK Biologicals Lack of scientific knowledge: we simply do not yet know
and PATH-MVI, should enter final phase III clinical trials in how to make a potent malaria vaccine. It is this, rather
2008, with anticipated registration as the world’s first than market forces, that is the single greatest barrier
partially effective malaria vaccine around 2012. holding back the field:
• The vast majority of vaccine candidates still fail either in
However, this apparently healthy global portfolio is deceptive.
the laboratory or at first clinical trial
Rather than reflecting a high level of early innovation with
• There is little or no likelihood that any new candidate
subsequent careful prioritisation and down-selection of
other than RTS,S will reach large-scale phase III clinical
candidates (leading to fewer but better candidates), the
trials by 2012
shape of today’s global portfolio is rather the unwitting
• Our best current bet, unless we see a breakthrough, is
product of scientific, technical and policy settings that
development of an RTS,S-plus combination vaccine
generate and promote candidates somewhat indiscriminately,
with greater efficacy; such a vaccine could be in field
with the vast majority subsequently failing in clinical trials.
trials by 2011-2013
Key factors increasing the number of malaria vaccine candi- Insufficient innovation in technology platforms, with over
dates in clinical trials include: half the current 47 candidates based on recombinant
technologies that are familiar but less likely to deliver a
An overall increase in activity from zero vaccines in clinical
high potency vaccine
trials in 1985 to 16 candidates today, and potentially up to
90% of current vaccine development projects are
31 vaccines in trials by 2009
conducted by public, not-for-profit and academic
A shift to “blood-stage” malaria vaccines, for which there
researchers who have innovation skills but may benefit
is no agreed artificial challenge test: all these candidates
from technical industrial assistance to translate their ideas
therefore normally go to field trials in Africa to test their
into safe, effective products
efficacy. Five times as many vaccines are now blood-stage
Lack of access to potent new adjuvants needed to boost
candidates than in 1995 (up from 11% to 56% of the
the efficacy of a vaccine candidate. Only five vaccine
global vaccine portfolio)
developers (representing around half of current clinical
Discovery of new malaria proteins (antigens), with 40% of
projects) have access to newer more potent adjuvants
current vaccine candidates and nearly half of emerging
PAGE
owned by companies; with the remaining 45% of clinical SECTION TWO: RESOURCE IMPLICATIONS
vaccine projects using older, weaker non-proprietary
Development cost
adjuvants.
The total direct cost for clinical development I of the malaria
Modelling the current malaria vaccine portfolio forward, and
vaccine and drug portfolio over the five-year period to 2012
applying these positive and negative forces, we begin to see
is estimated below; related manufacturing costs are also
what the future may hold. In particular:
assessedII. These costs will be partially offset by forward donor
Western trial demand will likely decrease due to the low commitments already made; and these are noted where
number of projects entering the clinic each year, based on known. In other cases, only donors are aware of what they
the size of the current preclinical portfolio have committed for the years ahead. In these cases, the size
The number of candidates in African field trials will of the funding gap can only be known if donors collectively
increase greatly, reflecting the higher proportion of blood- disclose their forward commitments, which can then be
stage candidates in development and the overall increase offset against the cost estimates below:
in candidates
US$88 million to US$126 million III for vaccine trials (plus
The number of vaccine projects in clinical trials is likely to
a known US$107 million pre-committed to the RTS,S
continue to increase over the next few years and stay at
vaccine in 2005 by the Bill & Melinda Gates Foundation)
relatively high levels for the foreseeable future
At least US$72 million for vaccine manufacturing IV
However, going forward, our modelling suggests that if
US$217 million to US$257 millionV for drug trials
five or less new projects enter early preclinical each year,
Up to US$184 million VI for drug manufacturing including
the summed impact will be a gradual decrease in total
toxicology.
clinical vaccine candidates over time.
These numbers will increase if additional preclinical research
These projections will alter if policy-makers and product
is funded and encouraged; and will decrease if greater coor-
developers introduce major changes, for example, agreement
dination is achieved by malaria product developers so that
to conduct challenge trials on all candidates (including blood-
fewer leads are progressed into field trials. Indeed, given
stage), or decisions that co-ordinate the global portfolio and
current initiatives to encourage greater global coordination,
therefore reduce the number of field trials needed.
we are hopeful that funding requirements will be at or below
The drug portfolio the lower end of our predicted scale.
The current drug portfolio includes 13 products in clinical trials Trial site demand and supply
and 8 candidates in preclinical. Around half these products are
Malaria products require very different trials - and trial sites -
being developed by Product Development Partnerships (47%),
at each stage of development. Taking these variations into
with the remainder coming from industry and public groups.
account, our assessment of licensure trial sites suggests that:
The uncoordinated nature of this activity - and the recent
The five Western institutions specialising in “challenge”
policy change to encourage use of artemisinin Combination
trials will be sufficient to meet global demand out to 2012
Therapies (ACTs) - means we now have a strikingly unbal-
if most or all are willing to subcontract out their services
anced “two-peak” global drug portfolio:
to product developers without challenge site access
Twice as many drug products are now in registration and The supply of malaria licensure sites in Africa is sufficient
clinical trials than in preclinical (the reverse of a normal to handle projected malaria product trials out to 2012 if
healthy pipeline) well managed. There is a network of 23 sites, including
There is a level of duplication, with six competing ACTs 18 current sites and a further 5 coming online by end
about to reach the market 2008. A further 14+ sites can conduct licensure standard
Policy-makers will imminently need to deal with a peak of drug trials with external support
ready-to-register products, including funding and Although overall site supply is sufficient, the lack of
managing phase IV trials for up to 12 drugs by 2011, each vaccine licensure sites in Nigeria may pose a problem for
needing to enrol tens of thousands of patients acceptance and delivery of a new malaria vaccine
Recent interest in supporting greater preclinical activity There are several capacity crunch-points that could
will result in a steady stream of drug projects going overload the trial network, particularly young trial sites
forward, as the portfolio gradually stabilises. with less experience, unless adequately anticipated and
I Defined as direct costs relating to clinical trials for licensure purposes, including per patient field costs and central trial management costs. These costs exclude overheads,
institutional costs or other indirect costs i.e. they are not meant to represent the total cost of maintaining the product development system
II Including process development, toxicology and stability studies, vialling, and batch manufacture
III US$103 million-US$148 million if adjusted for inflation and capital costs
IV US$81 million if adjusted for inflation and capital costs
V US$249 million to US$295 million if adjusted for inflation and capital costs
VI US$210 million if adjusted for inflation and capital costs
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managed. The years 2009-2010 will be particularly On-site staff training programmes
demanding due to a confluence of large trials. Diversification into multiple disease areas and products.
Phase IV trial site supply and demand for malaria drugs Notably, no successful mature sites were self-sustaining from
cannot be readily assessed, as there is not yet agreement on project income, despite product and funder diversification,
what should be included in phase IV programmes, how large with all stating that core funding was vital to their success
they should be, or who should conduct them. Therefore we and survival. This was largely because product developers
restrict ourselves to noting that whatever approach is chosen, routinely restrict overheads to half or less of real site overheads
it is likely to require enrolment of over 50,000 patients per (typically around 10-15% on overheads of 20-30%).
year in peak years (based on suggested phase IV programmes
A review of patterns of growth and investment for younger
to date); and that some of these enrolments may take place
sites shows that funders have not uniformly taken these
at licensure sites and will therefore need to be carefully
lessons on board. Investment in site upgrades has often gone
managed to avoid resource competition.
to sites with limited relevant experience, rather than sites
SECTION THREE: MANAGING THE TRIAL poised to move to the next step of the development pathway.
SITE NETWORK It was also striking that most young and new sites did not
have - and were not being funded to develop - the features
Funders and trial sites can justly congratulate themselves on
that characterise successful licensure sites:
their site capacity-building efforts in Africa. In 1995, there
were perhaps only six sites capable of licensure standard Few had affiliations with experienced sites or institutions
malaria product trials. However, in response to new R&D None received sufficient reliable core funding, with the
activity, seven new sites have been brought online since majority relying on project funding for 95% or more of
2001, with a further six sites due by end of 2008. These new their income. This restricted growth and diversification at
sites, with their high malaria loads and birth rates, will most sites
increasingly represent the future of malaria trials, but work is Most did not have an on-site training programme; and
needed to consolidate and add value to this network. had only a small staff of core PI’s
Younger sites had large malaria loads and high birth rates,
Maturing and sustaining young and new sites
but were being held back by lack of the financial and
Successful sites tend to follow a common development management skills needed to handle multiple simultane-
trajectory, moving from high-quality research studies to large- ous trials, funders and income streams.
scale intervention trials, drug licensure trials, vaccine licensure
Addressing these issues will help to consolidate new and
trials and, finally, diversifying into licensure trials in other
young sites, and to position them for upcoming malaria trials
diseases such as AIDS, TB or pneumonia. This organic growth
as well as for diversification into other disease areas.
pattern was seen by many sites as a key component of their
success. Maximising synergies between sites and trials
Time and cost to negotiate this growth trajectory was surpris- At a minimum, trials should be allocated to provide as close
ingly small, with examination of the seven recently upgraded a match as possible between the technical demands of the
sites suggesting that a typical site upgrade from research trial and the technical skills of the chosen site: having a high-
standard to licensure standard took around 2 years and cost tech site conduct a low-tech trial does not represent the best
around US$2 million. (Build up from scratch was longer, use of resources. If optimally allocated, product trials can also
taking around 5 years to reach licensure standard.) be a very effective tool to move sites up the development tra-
jectory, since each trial represents a significant injection of
Once at maturity, sites typically shared a set of common
cash and skills for a site.
features, all of which related to their operational and man-
agement capacity rather than to their size or site income. However, these maximum (and even minimum) benchmarks
These were: are not always met. It is not uncommon for donors and devel-
opers to simultaneously upgrade inexperienced sites to do
A long-standing relationship with a more experienced
complex licensure trials while more experienced (and
institution (usually Western)
expensive) licensure sites are being booked to conduct less
Long-term core funding
demanding phase IV trials. While phase IV trials do sometimes
A core staff of Principal Investigators (PI’s) with substantial
need to be conducted at licensure sites for sound policy or
licensure trial experience
PAGE
technical reasons, in other cases site selection is simply a these issues can be managed only with difficulty, due to the
reflexive reaching for the “best” site as opposed to the most lack of a central coordinating principle (as opposed to organ-
appropriate site. This type of misallocation generates multiple isation) to help product developers coordinate their plans.
inefficiencies including:
SECTION FOUR: VACCINE POLICY PRICE-TAGS
Direct competition for trial capacity at overloaded licensure
Different scientific and policy approaches have very different,
sites, at a time when these will be sorely needed for up-
coming phase IIb and III product trials (2009-10 particularly)
Lost capacity-building opportunities for sites at the start of
their development trajectory (e.g. non-licensure sites, drug
sites, and sites now being brought to small-scale licensure
standard)
Potentially increased costs since licensure sites are generally
more expensive to run.
Trial allocation also needs to be considered in light of the
fluctuating demand picture set out above. In particular, the
need to handle an upcoming stream of smaller drug and
vaccine trials (ideal for new sites); the need for young sites to
handle multiple larger trials, especially in 2009-10; the need
to manage competition between phase IV child and infant
enrolments and phase IIb vaccine trials; and, finally, the need
to ensure that young licensure sites are well placed to
diversify into other disease trials after 2010, when they will
have substantial spare licensure capacity. At the moment,
Figure A. Impact of a range of vaccine policy scenarios on cost and enrolments
VII RTS,S is excluded from all scenarios as its development programme is finalised i.e. it would simply appear as a fixed figure in every projection
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PAGE
Figure B. Cumulative candidates at 2012 under a range of SECTION FIVE: RECOMMENDATIONS

regulatory scenarios
We recommend that policy-makers and donors focus their
efforts on the three areas that are likely to deliver the greatest
efficiencies, the greatest improvement in overall product
development and the highest return on donor investment:
Provide sufficient funding for malaria product
development
As seen above, based on current portfolios, approaches and
policies, around US$561 million to US$639 million will
plausibly be needed to cover the outstanding costs of clinical
development and manufacture of new malaria drugs and
vaccines in the next five years. These figures will decrease in
response to major scientific or policy changes (coordination,
cooperation, a breakthrough candidate) and will increase if
negative scenarios eventuate (decreasing malaria and weak
vaccines).
These donor investments will be vital to promoting the global
product portfolio, however they will also generate substantial
opportunities in two areas:
African licensure sites will receive a very large injection of
funds. For vaccines alone, it will be around 60% of trial
spend (~US$122 million to US$146 million); with substantial
additional funds from drug trials. If managed well, this
could play a central role in consolidating the existing site
* For the simple development protocol there is one Ib/IIb trial in children and a
network and positioning it for the future
Ib/IIb trial in infants followed by another IIb in infants/children Up to around US$250 million in contract research and
manufacturing funding may be available to public and
private Contract Research Organisations (CROs), small phar-
Modelling suggests that the highest impact policy inter- maceutical firms, and developing country manufacturers.
ventions are all decisions that are well within our reach, in
A donor coordination exercise to assess their collective
particular improved coordination of global decision-
forward funding commitments would also allow these to be
making, reaching agreement on an acceptable challenge
assessed against projected costs, providing a clearer picture
model for blood-stage candidates, and streamlining the
of the funding gap.
regulatory pathway.
Consolidate the African network of malaria licensure
trial sites
In order to capitalise on investment in trial sites to date, as
well as the anticipated new product funding outlined above,
we recommend that donors and developers:
Shift their focus from building new malaria licensure sites
in Africa to sustaining and growing the capacity of the
present network of 23 sites VIII
Deliver a balanced funding stream by preferentially
allocating licensure trials to these 23 sites; and by providing
core funding for a minimum five years, perhaps starting
with the new and young “all purpose” licensure sites
(mature sites already receive core funding)
VIII We note again that Nigeria is the exception - see above and main text
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PAGE
Increase project overheads to levels suggested necessary Reduce technical barriers:
by full economic costing, if core funding is unpalatable
Provide formal industrial assistance to public and academic
Streamline project grant reporting and administration
product developers:
Provide all new and young licensure sites with support in
• Develop a public inventory of accessible public and
management and financial skills, either by expanding the
private vaccine manufacturing facilities, with ratings on
Malaria Clinical Trial Alliance (MCTA) to all sites or by
capacity, quality, cost, etc.
providing an additional service through the African
• Create incentives or policies to encourage collaborative
Malaria Network Trust (AMANET) and/or the European
R&D by public and academic groups and industry
and Developing Countries Clinical Trials Partnership (EDCTP)
• Provide a funding stream for contracted industry input
Fund a Clinical Trials Facility (CTF) at all vaccine licensure
to public candidates (ideally by leveraging the existing
sites (15-16 of the 23 sites), which could provide common
manufacturing expenditures, for example through the
financial, management and technical skills across all trials
proposed Industry R&D Facilitation Fund IX)
conducted by that site or centre; and potentially network
Improve access to potent adjuvants (e.g. the recent
CTFs across all sites
Wellcome Trust initiative).
Ensure all sites have an on-site staff training programme
Develop a formal mentoring system - and a linked proposal Remove policy barriers:
of formal training attachments - between younger sites
Improve co-ordination of global R&D and reach
and experienced African licensure sites, Western clinical
agreement on a challenge model for blood-stage vaccine
trial institutions and/or Western pharmaceutical firms
candidates; both high-return activities in terms of cutting
Ensure trials, including phase IV trials, are allocated to
costs and enrolments
avoid site competition and to maximise site progress along
Provide add-on funding for immunological studies
the development trajectory
alongside all trials (getting value from failure as well as
Co-ordinate proposed post-registration trials (phase IV,
from success)
ACT Consortium, Malaria in Pregnancy, etc.); and review
Provide additional resources to WHO to assist them in their
the possibility of head-to-head phase IV trials.
task of co-ordinating global malaria vaccine R&D, and
Other possibilities include: reaching common agreement on assays, endpoints and
protocols
Set up or build on a centralised information source on all
Rapidly clarify and codify a streamlined regulatory pathway
upcoming licensure and phase IV trials
to allow the global portfolio to move forward more quickly.
Develop an agreed minimum site audit template and/or
develop a shared Trial Site Audit service (perhaps CRO style)
Develop an African-based CRO to provide contract staff
for clinical trials, including experienced staff (training, data
management, monitors) and a pool of more junior staff,
to mitigate large employment swings at sites.
Build on the Malaria Vaccine Technology Roadmap
We highlight a number of proposals that build on the Road-
map recommendations.
Increase vaccine innovation:
Increase investment in basic research, including to avoid
shrinkage of the clinical portfolio over time
Support novel technology platforms by promoting
greater pairing of public malaria researchers with industry
innovators
Develop biotech-relevant policies and incentives to
support groups exploring higher-risk technologies (we will
publish a separate report on this in late 2007).
IX The IRFF proposal is outlined in Moran M, Ropars AL, Guzman J, Diaz J and Garrison C. The new landscape of neglected disease drug development. London School of
Economics and The Wellcome Trust. September 2005
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PAGE
PREFACE
Our brief was to quantify the resources needed for clinical development of the global
malaria product portfolio and to provide analysis to support more efficient allocation of
these resources. Typical questions we sought to answer included: “How big is the current
malaria product portfolio?”, “Where will it go in the future?”, “How much more trial site
capacity do we need?”, and, “When and where will investment be needed?”. Our project
was specifically tailored to fit in with priorities identified by stakeholders in the Malaria
Vaccine Technology Roadmap (the Roadmap)1. In particular, we sought to address Roadmap
requests that “trial site demand (by phase) should be forecast as accurately as possible”
and that “comparisons between the comprehensive site inventory and anticipated demand
(will be conducted) to…suggest a blueprint for endemic-region centers to begin site
planning and development efforts with stakeholder support”.
Our project focussed on clinical development, by which we variety of tools. Empirical data was collected on project
mean the process of taking a new product out of the labora- numbers and type, project attrition rates, and development
tory and through the years of testing in human subjects that pathways of known malaria drug and vaccine projects since
are needed to register it on the market. Analysis included 1985 X. This data was supplemented by extensive interviews
manufacturing and toxicology related to preparation and with funders, product developers, vaccinologists, malaria
testing of trial product; and preclinical to the extent that it experts, and clinical trial site directors: where quoted, their
acted as a “feeder” for the clinical portfolio. Post-registration comments were anonymised to protect confidentiality. A
trials were also included to the extent possible, allowing for simulation model, developed in conjunction with colleagues
the high level of current uncertainty in this area. Basic and at the University of Oxford, was also used to generate
discovery research were by definition excluded from our brief, scenarios of possible outcomes based on this data, including
although we recognise their importance in fuelling the likely product numbers, cost, trial burden and enrolment
product pipeline. demand over the five-year period to 2012. Finally, our findings
and analysis were discussed and reviewed by a high-level
Our focus was on malaria vaccine development targeted at
group of product developers prior to concluding our report.
P. falciparum in Africa, and on drug development targeted at
P. falciparum and P. vivax. We did not include product R&D We made a particular effort to balance scientific complexities
that we believed had a lower likelihood of being prioritised with policy realities. This was vital, since the variety of cause
for developing country rollout, such as prophylactic anti-malarial and effect in the malaria field play a key role in determining
drugs and transmission blocking malaria vaccines. Our whether R&D policies will succeed or fail. We sought to
analysis was also restricted to the five-year period to 2012, capture this complexity, but to clarify and simplify it to give
reflecting the widespread view of malaria experts and product policy-makers and funders a picture of what they might rea-
developers that the rapid evolution of science, technology, sonably expect in the future and what this might cost. For
and regulatory settings (for vaccine development in particu- instance, we modelled the likely impact of a range of scien-
lar) meant that longer timelines were unrealistic and would tific, technical, policy, and regulatory choices in order to
reduce rather than increase the reliability and usefulness of provide a clearer understanding of their impact on cost, trial
our modelled outcomes. sites, and overall development of the malaria product
portfolio. (Going forward, this model will ideally be used as a
Answering the questions noted above required a range of
dynamic tool to assess the impact of new developments and
strategies. Some aspects, such as the number of drug
policies, with outcomes in turn being used to refine and
products in development, were readily assessed but others
modify the model itself.)
offered slippery analytical targets. For instance, no malaria
vaccine has ever been brought to registration so there was no We hope that this picture of the malaria product field, and of
fixed development pathway to use as a guide, and informa- where and how it could be advanced, will prove useful to
tion on malaria vaccine failure rates (attrition rates) at each those funders whose contributions offer ongoing hope to the
stage was limited. We dealt with these uncertainties using a many millions suffering from malaria.
X Empirical drug data was also available from our previous work. Moran M, Ropars AL, Guzman J, Diaz J and Garrison C. The new landscape of neglected disease drug
development. London School of Economics and The Wellcome Trust. September 2005
13
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BACKGROUND TO
CLINICAL DEVELOPMENT
One needs some understanding of the science behind malaria product development if
effective policies and funding streams are to be put in place. This means both a broad
understanding of the process that moves potential new products from the laboratory
to the market, and a specific understanding that malaria drug and vaccine development
are two completely different animals in terms of cost, risk, and development pathways.
A policy intended to suit both drugs and vaccines is unlikely to be either effective or
correctly sized.
Malaria vaccine development represents something of an Beyond these undoubted difficulties, malaria vaccines also
unknown quantity. The malaria parasite presents a difficult present a number of specific scientific challenges related to
and changing target immunologically; malaria antigens and the type of vaccine. Different types are targeted at different
vaccine technologies are still being discovered; regulatory stages of the parasite life cycle including: pre-erythrocytic
pathways are being developed on the go (since no malaria vaccines, theoretically aimed at inducing an immune response
vaccine has ever been registered); and product developers that completely prevents the establishment of infection (also
have little idea of what “normal” vaccine attrition rates might called sterile immunity); blood-stage vaccines, aimed at
be, apart from a suspicion that they are very high. controlling parasite infection rates in the blood thereby
Development risk is high because vaccines are trialled in preventing disease or death; transmission-blocking vaccines,
healthy children and infants, where side-effects or serious which do not prevent the vaccinated individual from
adverse events cannot be offset against the value of the cure. contracting malaria but prevent them from transmitting it to
Manufacturing requires a dedicated specialist plant and once others; and multi-stage vaccines, which combine two or more
manufactured there is no established malaria vaccine market of the previous types.
(or even the concept of a malaria vaccine in much of Africa).
These different vaccine types have somewhat different
Malaria vaccine trials are larger, longer and more expensive
development pathways, with the most important distinction
than drug trials: even early trials can involve several thousand
being that pre-erythrocytic vaccines have the advantage of a
participants and final licensure trials may need upwards of
defined artificial “challenge test” (also called a phase IIa trial).
12,000-15,000 subjects, many of whom will need to be
In this test, a small number of malaria naïve Western volunteers
monitored for two or more years.
are vaccinated prior to exposure to malaria-infected
Vaccine candidates essentially use humans as their testing mosquitoes under controlled conditions, to see whether or
ground, unlike drug candidates, which can be optimised in not they subsequently develop parasites in the blood
animal and in vitro (laboratory) tests prior to human testing. (parasitemia). This test gives a strong indication of how
The lack of animal vaccine models to produce direct and efficacious a candidate is and therefore helps terminate
reliable predictions of likely human outcomes, and a lack of projects early in the development process, before going to
in vitro markers for immunity means that product developers “the field”. No such test has been validated for blood-stage
only know how efficacious a vaccine candidate really is once candidates; instead, they are normally tested in African field
it is injected into humans and exposed to malaria. As a result, trials to determine their efficacy.
vaccine candidates generally go through an iterative develop-
In comparison with vaccines, malaria drug development is
ment process: being tested in small human trials, going back
essentially a known quantity. Anti-malarial drug targets are
to the laboratory for re-formulating (e.g. combination with a
known, the science of drug development is understood,
new adjuvant), being trialled again and so forth until the
regulatory pathways are well established, and known attrition
optimum formulation and desired effect is reached, at which
rates for drug development provide a useful guide for
point the candidate moves into more advanced human trials.
portfolio planning2. Development risk is substantially lower
Here, the candidate needs to be tested sequentially in
for drugs than vaccines because of the smaller investment
different patient groups: first going through trials in Western
needed and the fact that malaria drugs are given only to the
adults, then in African adults, young children and finally, to
sick (unlike vaccines where healthy children receive the
trials in the target infant group.
end-product). The field for new malaria drugs has also been
14
PAGE
well prepared: the concept of malaria drug treatment is

entrenched throughout the developing world; anti-malarial
drug markets are thriving, if not particularly lucrative; and
manufacturing facilities are readily available (albeit sometimes A policy
of varying quality). intended to
suit both drugs
It is also important to note that the drug candidate that goes
into clinical trials is almost always the same product that will
and vaccines is
come out at the other end; that is, the candidate is selected, unlikely to be
optimised, and finalised prior to trials in humans. Malaria either effective
drug trials are short, sometimes only needing 28-day patient or correctly
follow-up, trial numbers are small, ranging from a few sized
hundred to a few thousand subjects, and rolling enrolment is
possible; therefore, demand for funding and trial sites is com-
mensurately moderate. A modest degree of complexity and
cost has been added by a recent policy change to artemisinin
Combination Therapies (ACTs) as first-line drug therapy,
which means that anti-malarial drugs must now be
developed as combination products rather than stand-alone
treatments as was the case in the past. Nevertheless, malaria
drug development remains substantially less complex than
malaria vaccine development.
15
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THE CURRENT AND 01
> 01 FUTURE MALARIA
SECTION
PRODUCT PORTFOLIO
In order to have a clearer idea of what the future holds, we need information on
several points. We need to know what is in our current malaria product portfolio, what
development pathway these products are likely to follow, and what forces are moving
products down this pathway or, conversely, holding them back. Using this information,
we can begin to draw a picture of the future: How many products are likely to be in
development at each point in time? How many trials will be needed each year? What kind
of trials these are likely to be? This is the first step to anticipating resource demands over
the next five years and planning how and where these resources might best be allocated.
Figure 1. Global malaria vaccine portfolio in November 2006 (n=47)

1.1 MALARIA VACCINES
As of November 2006, the global malaria vaccine portfolio
included 47 candidates, including 31 in preclinical develop-
ment and 16 in clinical trials (see Figure 1 and Annexe 1b and
1c). Due to differing methodologies, this number is substan-
tially lower than the 72 vaccine candidates in the 2006
Rainbow List 3 (46 preclinical and 26 clinical). (See Annexe
2 on Methodology).
At first sight, this global portfolio looks promising, demon-
strating the healthy “triangular” shaped pipeline of a
well-structured product portfolio. There are a large body of
early candidates, which are then whittled down to a handful
of clinical candidates and finally to one or two late-stage
products. Unfortunately, this appearance is deceptive. The
portfolio does not reflect high early innovation followed by
well-coordinated, evidence-based deselection of inferior
candidates to leave one or two front-runners. Rather, the
triangular shape of today’s pipeline is the unwitting product
of scientific and technical gaps or deficits that have collective-
ly conspired to push many candidates through to the clinic
(high early activity), where the majority subsequently fail (few
late-stage products).
1.1.1 THE VACCINE DEVELOPMENT PATHWAY

As noted previously, the clinical development pathway along
which vaccine candidates must travel is far more complex and
iterative than the drug development pathway, taking up to
11 to 15 years to complete. Not only does the early vaccine
candidate move from small phase I human trials back to the
laboratory for re-tooling and back again into human trials, but
phase I and/or II trials are also sequentially repeated in
Western adults, African adults and African children before the
candidate finally enters trials in the target infant group (see
Figure 2). Once registered, very large phase IV post-registration
trials will also be needed, however as these fall outside the
time frame of this project, they are not discussed further.
16 T H E C U R R E N T A N D F U T U R E M A L A R I A P O RT F O L I O > T H E M A L A R I A P R O D U C T P I P E L I N E
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Figure 2. Simplified standard phase I-III development plan for malaria vaccines (see Annexe 3b for complete plan)
ADULTS CHILDREN INFANTS
2-3 YEARS –––––––––––––––––––––––––> 2-3 YEARS –––––––––––––––––––––––––> 2-5 YEARS** –––––––––––––––––––––––––> 5 YEARS –––––––––––––>
phase Ia/IIa* phase Ib phase Ib phase IIb phase Ib phase IIb phase III
- 2 x safety - safety and - safety and - proof of concept - safety and - safety and - large pivotal trial plus
studies immunogenicity immunogenicity trial immunogenicity efficacy studies several smaller trials in
- non endemic study study - endemic study (including proof subgroups
country - endemic - endemic country - endemic of concept and - multicentre, around
country country country bridging studies) 8-9 African countries
- endemic country
Candidates may be reformulated and re-trialled
* Blood-stage vaccines will likely skip a phase IIa challenge and in this case, the phase Ia/IIa described above will be a phase Ia only
** A longer timeframe may be needed in specific cases e.g. if a different purification process is needed
1.1.2 FORCES ALONG THE DEVELOPMENT FORCES THAT PROMOTE PROGRESS OF MALARIA
PATHWAY VACCINE CANDIDATES
A range of forces determines the movement of vaccine can- Increased research activity
didates into and along this clinical development pathway (see
Interest in creating a malaria vaccine has grown over the past
Figure 3). The collective impact of these forces in generating
10-15 years, particularly with the discovery of new antigens
or terminating projects manifests itself as “attrition rates”,
and technologies and the injection of new funding from
that is, the likelihood of a project transitioning from one
donors. As a result, the global portfolio has expanded from
phase of development to the next.
having no malaria vaccines in clinical trials in 1985 to the
At first glance, forces that promote projects through the current situation where sixteen candidates are in trials (see
clinical pipeline would seem to be an undiluted good, while Figure 4 and Annexe 1c). Applying attrition rates to this
retardant forces would be undesirable. However, this portfolio going forwards suggests we may have up to
understanding is wrong. Forces may promote undeserving 31 vaccine candidates in clinical trials by 2009. This includes
candidates (rather than strong candidates), while retardant the 16 candidates now in trials and up to an additional 15
forces are often the main agent removing weak candidates candidates that may make it out of preclinical development
from the field. Forces have the greatest net positive impact and into the field by that time.
when they selectively terminate weaker projects (the
This constitutes a marked increase in malaria vaccine candi-
majority) and promote stronger projects (perhaps a handful at
dates since the mid-1980’s and even in the past ten years.
most), resulting in fewer but better candidates.
T H E C U R R E N T A N D F U T U R E M A L A R I A P O RT F O L I O > T H E M A L A R I A P R O D U C T P I P E L I N E 17
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Figure 3. Forces that promote or retard malaria vaccine development
The clinical
malaria vaccine
portfolio will Figure 4. Malaria vaccine portfolio in the past 20 years
nearly double
by 2009
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Figure 5. Malaria vaccine types in development in 1995 and 2006
A shift to blood-stage candidates Increased antigen diversity

In the past, vaccine portfolios were dominated by pre-ery- Researchers are exploring more antigens in an effort to
throcytic and multi-stage candidates: eight of the nine clinical increase vaccine potency.
candidates in the 1995 snapshot were either pre-erythrocytic
Ten years ago, all clinical vaccine candidates were based on
or multi-stage candidates, as were 82% of clinical projects
the three main antigens discovered in the late seventies and
terminated between 1985 and 2006. The availability of an
early eighties (CSP5, MSP-16 and AMA-17 ), and more than
artificial “challenge test” for these types of vaccines meant
half were single antigen vaccines based on CSP (5 of the
that poorly immunogenic candidates were identified and
9 vaccines in clinical trials). (See Figure 6).
terminated before reaching African field trials.
However, two new trends are now emerging. Firstly, the three
Today’s portfolio has, however, shifted towards blood-stage
well known antigens are gradually being displaced by more
candidates at both the clinical and preclinical stages (see
recently-discovered antigens including, LSA-1 and LSA-3,
Figure 5).
GLURP, STARP, and MSP-3, at both the clinical and preclinical
This shift very significantly increases demand for field trials for level. Secondly, product developers are increasingly moving to
two reasons: first, because there are more candidates; and include many more antigens in each vaccine, with multianti-
second, because there is no agreed human challenge model gen candidates now making up 37% of the clinical trials and
for blood-stage vaccines4. Various blood-stage challenge tests 45% of the preclinical portfolio. Overall, around 40% of
do exist and have been used in Australia and the UK but there current clinical candidates and nearly half of current preclinical
is not yet scientific agreement as to which approach is best, candidates now include novel antigens discovered in the last
nor have ethical questions been resolved around injecting 10-15 years.
blood into healthy patients (which such a challenge would
We note, however, that the science is still out on the role of
require). Therefore the only way to know if a blood-stage
antigen diversity in creating more potent vaccine candidates.
vaccine works is to test it in field trials in endemic countries.
Some argue in favour of this approach: “… a handful of
As a result, we can expect to see a far higher percentage of
antigens have been tried in so many different forms with no
candidates going to field “challenge” in the five-year period
success … more money should be allocated to antigen
to 2012.
discovery programs”. While others feel that: “We don’t need
many more portfolios of proteins … the ones currently
available should be able to deliver a suitable vaccine”.
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Figure 6. Antigen use among malaria vaccines in development in 1995 and 2006
* All based on CSP # A total of 13 antigens represented ^ A total of 16 antigens represented
Lack of tools to identify the best candidates immune to malaria (immunological studies attached to
trials would help move towards this goal); and animal
There are now many more malaria vaccine candidates in
models that mimicked the human immune response to a
development than at any time in the past twenty years. Given
vaccine candidate.
this, as spelt out in the Roadmap, funders would greatly
benefit from a more closely co-ordinated approach to trial All of these ideas have been well covered in the Roadmap,
design and measurement to help identify potential winners which remains a useful reference point for malaria product
among these new candidates, including: developers and funders. As seen from Tables 1 and 2, there
has been progress on many of the activities identified by the
Creation and standardisation of assays, reagents and
Roadmap, although this has been in a largely uncoordinated
protocols used at each stage of malaria vaccine product
manner. Scientific agreement on assays has not yet been
development
reached i.e. assays are being developed but without general
A shared set of vaccine ranking criteria based on “safety,
agreement on their use or value; while WHO’s efforts to
type of immune response induced, ability to generate a
coordinate across continents have also moved ahead slowly,
functional antigen, potential formulations, and manufac-
largely due to lack of staff and resources. These remain
turability”1
important stumbling blocks in progress towards the best
If these tools could be agreed on and implemented,
possible malaria vaccine.
funders could compare results across trials to see which
candidates performed best; and could cross-reference In other areas, there has been demonstrable positive change,
positive and negative results across candidates. This would including several new trans-Atlantic initiatives to improve
allow positive spin-offs to accrue even if a vaccine trial coordination of R&D decisions and the global portfolio. We
failed. Nevertheless, some donors do not provide funding particularly note the proposed candidate coordination
for “add-on” immunological tests in a (probably false) discussions between EMVI, MVI, and USAID on common
economy aimed at cutting costs. Beyond the more readily guidelines for candidate prioritisation at go / no go points in
available efficiencies generated by funder and researcher vaccine development.
co-ordination, malaria vaccine development would also
benefit from having tools to identify potentially successful
vaccines in the laboratory or in smaller clinical trials. Of
particular use would be correlates of protection i.e.
markers that show that a vaccinated patient has become
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Table 1. Progress on the development of “…standardised “tool kits” of validated assays, reagents and operating procedures…“
(Roadmap Initiative 3)1
TECHNICAL
Growth Inhibition Assay (GIA) (MVDB) The MVDB, part of the NIH (NIAID), has developed a GIA assay
Funded by NIH/MVI and protocol, standardised for certain blood-stage vaccine candidates.
However, not all scientists agree on the wider applicability of the GIA approach,
although groups including EMVI and USAID are interested in using it
GIA Reference Center (NIAID) The Reference Centre, recently relocated within the NIAID, will make the
Funded by MVI GIA assay protocol and reference reagents, developed and used by the MVDB,
available to organisations outside the NIH to test their vaccine candidates.
An MVI agreement with the Centre provides funding for ~ 1,000 samples
per year to be tested
The Antibody-Dependent Cellular The Institut Pasteur is optimising and standardising an assay for testing
Inhibition (ADCI) assay (Pasteur) a range of vaccine types with the aim of delivering a reliable and consistent
test of vaccine immunogenicity. However, support for this approach
is reduced by its lack of reproducibility to date
Afro-Immunoassay Network (AIA) A network of 6 African laboratories, coordinated from the Noguchi
Funded by AMANET and the Memorial Institute for Medical Research, Ghana. It has standardised
Netherlands Ministry of Foreign Affairs immunological assays for blood-stage vaccine antigens (e.g. AMA1,
MSP1-19, MSP3 and GLURP) to enable comparison between trials.
The AIA plans to expand to include a wider range of antigens and
additional African partners
ELISA Service Center (WRAIR) The Malaria Serology Laboratory (MSL) at the WRAIR has several ELISA-based
Funded by WRAIR, USAID and MVI assays, originally developed for antigens used in vaccines being developed
by the WRAIR. These assays have been optimised for sensitivity, and are
proceeding toward full validation. Vaccine developers using the same
antigens are able to send samples to the MSL and have access to
standardised, blinded testing
POLICY
Initiative on Optimising Malaria Vaccine Convened by WHO in November 2004, this group has addressed issues
Lab Assays Evaluation (OPTIMALVAC) relating to assay standardisation, and recommended formation of an
assay working group, the Malaria Vaccine Lab Assays Working group (MVLAW*)
Proposal for an Assay Harmonization This group follows on from the proposed (but as yet unfunded) MVLAW
and Standardisation Initiative group, which planned to cover humoral assay standardisation (e.g. ELISAs),
WHO/IVR, EMVI and MVI functional assay standardisation (e.g. GIA and ADCI), and cell-mediated
inhibition assays
European Network for Harmonisation of This EMVI-led network aims to develop, optimise and standardise a range
Malaria Vaccine Development (EURHAVAC) of reliable assays to be used in early pre-clinical, and clinical studies
Funded by EC FP6
T-cell assay meeting To discuss a joint approach to T-cell assay development. Associated with
Funded by MVI the MVW Conference in London in September 2007
* The Malaria Vaccine Lab Assays Working Group (WHO/IVR), initially funded by NIH, USAID and the Monte dei Paschi di Siena Foundation, was initiated in
September 2005 to address assay development, optimisation, validation and standardisation. Priority actions and groups were identified but this initiative did
not receive follow-on funding
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Table 2. Progress on the development of “…a common set of measurable criteria, linked to strategic goals, to guide scientific and
investment decisions at various stages along the entire vaccine development process” (Roadmap Initiative 6)1
WHO Study Group on Measures of In October 2006, WHO convened an expert meeting to discuss methods
Malaria Vaccine Efficacy for evaluating the efficacy of malaria vaccines in phase III trials, the results
Funded by WHO/IVR, MVI and the of which have recently been published and have formed the basis for the
Monte dei Paschi di Siena Foundation selection and definition of end points for the RTS,S vaccine phase III pivotal
trial. The group’s next focus will be on improving phase IIb trial design, as
well as assessing the challenge model for pre-erythrocytic vaccines as a
selective process for vaccine candidates
European Network for Harmonisation of In addition to the above, EURHAVAC aims to design a clinical development
Malaria Vaccine Development strategy by defining go/no go criteria for preclinical candidates moving into
(EURHAVAC) clinical trials, and by defining and standardising safety and immunological
Funded by EC FP6 evaluation criteria
European Malaria Vaccine Development A European collaboration of 2 SMEs, 8 malaria vaccine research centres,
Association (EMVDA) EMVI and AMANET, whose key goal is to identify antigens with potential as
Funded by EC FP6 candidate vaccines and to move these as quickly as possible into clinical
studies. EMVDA notes that clear criteria for progression are inherent in this
concept, and has a work package focussed on cross-cutting issues including
vaccine evaluation
EMVI/ MVI/ USAID blood-stage To be held at the end of 2007, to discuss coordination and prioritisation
candidate meeting of blood-stage malaria vaccine candidates between these European and
US-based groups
EC/AIDCO-sponsored consultancy EC-AIDCO sponsored consultancy group, commissioned to develop guidance

criteria for selection and prioritisation of candidate vaccines for AMANET -
sponsored trials
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FORCES THAT RETARD PROGRESS OF MALARIA greatest contributor to limiting demand for large-scale
VACCINE CANDIDATES vaccine trial conduct or funding, since modelling suggests
there is little or no likelihood that any current candidate
The dominant force retarding the progress of malaria vaccine
(other than RTS,S) will reach phase III trials by 2012. A
candidates is the relatively weak state of science and technol-
more likely outcome is that one of the current batch of
ogy in the field, which means the majority of projects are too
vaccine candidates will prove sufficiently immunogenic and
weak to clear the potency and safety hurdles needed to move
efficacious to be taken back and re-developed as a combina-
into later stages of clinical development. In other words,
tion vaccine with RTS,S (this depends, however, on GSK); or
science and technology barriers help to weed out weaker
that a new up-and-coming candidate proves to be highly effi-
candidates but also mean stronger candidates are not there
cacious and is preferentially moved ahead. Even so, neither of
to take their place.
these approaches would be likely to see a new candidate in
Scientific barriers phase III by 2012.
An examination of malaria vaccine candidates developed
Technology barriers
between 1985 and end-2006 shows that more than 80%
Three technology barriers were identified as particularly
have not reached field trials in malaria-endemic countries.
problematic: insufficient innovation in vaccine technology
The vast majority failed either in the laboratory or at their first
platforms; lack of vaccine production skills; and lack of access
safety and “challenge” tests in the West (see Figure 7).
to potent adjuvants.
At the macro level, this scenario has not substantially
Insufficient innovation in technology platforms
changed. Despite their best efforts, scientists still do not
know how to make a potent malaria vaccine, and failure will The potency of new vaccines is limited by the paucity of
continue to be the norm rather than the exception for the innovative approaches to vaccine construction. Recombinant
foreseeable future. The current front-runner, RTS,S, has protein technologies continue to be the most familiar and
demonstrated ~30% efficacy for the first clinical episode of most popular vaccine platform, representing over half of the
malariaXI, 8. While this is a good step forward, it is widely current 47 clinical and preclinical projects in the global
believed that a significantly more potent malaria vaccine is portfolio (see Figure 8). While this technological approach
many years away. For instance, the Malaria Vaccine increases the likelihood that a vaccine candidate will be
Technology Roadmap aims at licensing a malaria vaccine able “make-able”, some scientists believe there is a limit to the
to reduce clinical malaria by 80% by 20251. potency of any recombinant vaccine using current antigens,
even with the addition of ever more powerful adjuvants.
It is these scientific barriers, rather than market forces or lack
of trial sites, that are the single largest hurdle to development Given this limitation, it would be encouraging to see a greater
of a successful malaria vaccine. These barriers are also the trend towards new technology platforms that may hold the
Figure 7. The global malaria vaccine portfolio from 1985 to 2006
No candidate
other than
RTS,S will
reach phase III
trials by 2012
XI Vaccine efficacy for time to first clinical episode was reported as a reduction in risk of 29.9% over a 6-month surveillance period, with a 95% CI of 11.0-44.8
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Figure 8. Malaria vaccines in development in 1995 and 2006 by technology platform
* Other includes irradiated and genetically attenuated sporozites and DNA vaccines
answer to increased vaccine potency. As noted in the documented if the goal is successful scale-up of a candidate
Roadmap: “…combination, live-vectored, and attenuated to a stable, reproducible product.
whole-parasite approaches … may ultimately offer the most
Today, these skills still reside primarily with industry. This is
potential for highly effective vaccines capable of providing
particularly important to note given that non-industry groups
long-term protection”. Although such a trend cannot be seen
are still the main drivers of malaria vaccine R&D (see Figure 9).
from the data presented in Figure 8, we note that some groups
A comparison of vaccine projects in clinical development in
(e.g. the NIHXII, NMRC, University of Oxford and University of
1995 with those in clinical development today shows that,
Lausanne) have made a conscious decision to focus on
although project numbers have nearly doubled, purely indus-
applying new technologies or technologies not previously
trial malaria vaccine development still represents only around
used for malaria vaccines e.g. adenovirus vectors, prime boost
10% of total projects. By contrast, public vaccine R&D
approaches and synthetic peptides, and that this may translate
(originally largely the preserve of the U.S. Department of
into new technologies going to the field in the future.
Defence and the NIH) is increasing, for example by academic
Lack of production skills researchers based at the University of Oxford, Institut Pasteur
and the University of Lausanne.
Many public and academic developers want to make a
product-like vaccine but may not have the in-house process Some “non-industry” groups are not yet focussed on
development, scale-up and formulation capabilities, and production issues. Others address production hurdles by using
Good Manufacturing Practice (GMP) production experience subcontractors or seeking formal industry partners. There are
to do so. In order to become a registerable vaccine, a product several examples of successful vaccine manufacturing
in the laboratory must move to larger GMP lots to support collaborations, including those between WRAIR and GSK Bio;
phase I and II trials (a “scale up” from 10 or less litres to 100 MVI and Shanghai Wanxing Bio-Pharmaceuticals; NMRC and
litre scale), and ultimately be able to be produced in quanti- GenVec; and MVDB and the WRAIR Pilot Bioproduction
ties large enough to support post-licensure requirements Facility. However, this process is far from perfect across-the-
(1000s of litres) without any of the changes in potency, board, and there are a number of examples where
stability, and efficacy that can occur during scale-up in the manufacturing difficulties have held back the preclinical
manufacturing process. (Although “scale up” generally development of a candidate malaria vaccine, for example:
means full commercial scale-up, in this report we use the
Vaccines have failed to meet batch-to-batch reproducibility
term to refer to the first smaller production increase, since
The technology platform chosen may not be the most
most current vaccine candidates will not go beyond this).
appropriate and ultimately faces production, safety or
Technical feasibility must also be carefully examined during
regulatory issues (e.g. long synthetic peptides). This leads
preclinical development, and assays and other standard
to significant delays in developing and field testing the
operating procedures need to be sufficiently developed and
candidate while new expression systems are sought
XII This refers to the The Division of Microbiology and Infectious Diseases (DMID) at the NIH, which supports extramural research on malaria vaccines
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Figure 9. Malaria vaccines in clinical development in 1995 and 2006 by lead doer type
* SME = small to medium enterprises
Companies contracted to develop or scale-up the manu- the projects currently in clinical development and 55% of
facturing process change focus, cannot meet the historical vaccine clinical candidates have been formulated
manufacturing demands, or pull-out of the contract for with alum-based adjuvants. Alum-based adjuvants are,
other reasons (e.g. IP issues), thereby delaying the project however, less immunogenic than more novel adjuvants and
timelines (e.g. MSP-2 3D7+ MSP-2 FC29 E. coli, MSP-4 E. some malaria vaccine product developers are moving away
coli, LSA-3 long synthetic peptide, RAP-2 E. coli-expressed, from them. For instance, of the known preclinical vaccine
GLURP long synthetic peptide, HBCAg-CSP VL and MSP- candidates requiring an adjuvant, only around 30% use
119 baculovirus-expressed) alum-based formulations.
The available industrial partner or Contract Research
However, although more immunogenic adjuvants are now
Organisation (CRO) does not have the know-how to make
available, they are not accessible to all malaria vaccine
the final product, so developers must continually build
developers. Adjuvants, like vaccines, are an expensive and
expertise and long learning curves are experienced (e.g.
high-risk technology to develop, involving significant invest-
RAP-2 E. coli-expressed)
ment by the pharmaceutical or biotech companies who
The technology being tested is novel and the facilities to
develop them, and who then control access to their use. Only
make the final product are not available, so a larger upfront
five vaccine developers are able to use new adjuvants owned
investment is needed, thereby delaying development
by companies, with these five accounting for around half
times (e.g. the attenuated sporozoite vaccine).
(55%) of current clinical formulations and around one third
Failing adjuvants and lack of access to newer, more of current preclinical formulations. Several product develop-
potent ones ers interviewed commented on the key obstacles to accessing
adjuvants. These included: inability to successfully negotiate
An adjuvant is a compound used to enhance the immune
with adjuvant developers; strict conditions imposed on
response to a vaccine or, in some cases, to reduce the amount
laboratory standards and procedures when working with the
of vaccine needed to elicit the desired response9.
adjuvant; and lack of familiarity in dealing with intellectual
Alum-based adjuvantsXIII are the most commonly used in property issues. Several groups interviewed had experienced
malaria vaccine development. Alum has been available for changes and delays in their portfolios caused by failed
vaccine development for 60 years10, and its properties are well adjuvant negotiations, while others had decided to use a
known. It is considered safe, non-toxic, and appropriate for potentially less potent commercially available adjuvant purely
developing country use as it is stable and cheap to manufac- to avoid these issues.
ture10. Furthermore, alum-based adjuvants are readily
available to all malaria vaccine developers. In fact, 45%XIV of
XIII Including aluminium hydroxide, alhydrogel, and aluminium phosphate; as well as any of these plus another component (including MPL, QS21, or CPG 7909)
XIV For the current portfolio, this figure includes formulations using Alum + CPG 7909 (CPG 7909 is proprietary)
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1.1.3 THE VACCINE FUTURE and number of trials generated by these projects, whether or
not these trials will be conducted in the field, and how large
When the current vaccine portfolio is fed through the clinical
these trials are likely to be. We have therefore modelled the
development pathway and subjected to attrition due to the
likely number of new trials generated by the current project
forces discussed above, we begin to get a picture of what the
portfolio, and broken these down into three categories based
future may look like. This picture is outlined below to provide
on their resource implications:
policy-makers and funders with a set of likely planning
parameters, and to forewarn them of funding and site demand Western trials (the small safety and challenge tests that
fluctuations they may need to plan for. precede a vaccine candidate’s introduction to African
field sites)
The future vaccine product portfolio
Small field trials (initial African safety trials of less than
Modelling the current portfolio forward suggests that the 60 subjects that precede wider testing)
number of vaccine projects in clinical trials is likely to continue Large African field trials (safety and preliminary efficacy
to increase for the next few years and to stay at relatively high trials in several hundred to several thousand patients). This
levels for the foreseeable future (see Figure 10A). However, category includes phase IIb trials, as well as the only phase
the breakdown of projects is likely to change, with a shift III trials that will take place in the next 5 years, these being
towards projects in Africa and away from Western projects, the RTS,S trials scheduled to commence in Q2/Q3 of 2008.
for reasons discussed below (see Figure 10B).
As seen in Figure 11 and Table 3, demand for both small and
The future vaccine trial burden large trials in Africa is likely to be significant going forward,
including perhaps 8-9 new small African safety trials and up
While it is helpful to have a picture of the likely number of
to 4 larger trials in most years.
projects going forward, this alone can be somewhat mislead-
ing. The characteristics that fundamentally dictate future
resource needs are not project numbers but rather the type
Figure 10A. Projected total number of clinical malaria vaccine Figure 10B. Projected total clinical malaria vaccine projects over
projects over five years five years by trial location
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Figure 11. Projected number of new malaria vaccine trials over However, going forward, our modelling suggests that if
five years five or less new projects enter preclinical each year, the
summed impact under any scenario will be a gradual
decrease in total clinical vaccine candidates over time.
These projections will alter significantly if policy-makers and
product developers introduce major changes. For example,
agreement to conduct challenge trials on all candidates
(including blood-stage) will increase Western trial numbers
substantially; while the number of large field trials would be
dramatically reduced by agreement to co-ordinate the global
portfolio and therefore decrease the number of candidates
going to the field.
As noted above, the framework and model developed for this
project are also available as a dynamic tool to assess the
impact of such changes, with some preliminary scenarios
modelled in Section Four.
1.2 MALARIA DRUGS

The current malaria drug portfolio includes 13 products
already in clinical trials and 8 pre-clinical candidates that
could enter clinical trials in the next five years (see Figure
12 and Annexe 1a). This includes:
6 artemisinin Combination Therapies (ACTs) for treatment
of uncomplicated P. falciparum malaria (Chlorproguanil-
Table 3. Projected cumulative new field trials at year 5 (2012) Dapsone-Artesunate, DHA piperaquine, Pyramax (also
being trialled for P. vivax), AS/AQ, AS/MQ and ferroquine-
Range Applying a mid- artesunate). While all are suitable for treatment of infants
point attrition rate
from 6 months of age, only Pyramax will be available in a
Small field trials 36 - 50 40
paediatric formulation
Large field trials 15 - 20 19
1 paediatric ACT formulation for treatment of uncompli-
Large field trials (excluding RTS,S) 9 - 14 13
cated P. falciparum in infants (Coartem Dispersible)
2 non-ACT combination therapies for treatment of uncom-
plicated P. falciparum malaria (fosmidomycin-clindamycin
and AQ13). Not in paediatric formulations
3 monotherapies for severe P. falciparum malaria, where
Even a quick glance over these figures shows that, as matters
oral treatment may not be possible (rectal artesunate,
stand:
rectal quinine, IV artesunate)
Western trial demand is likely to decrease due to the low 1 non-ACT therapy, initially in development for treatment
number of projects entering the clinic each year, based on of uncomplicated P. falciparum malaria, but now being
the size of the current preclinical portfolio considered for other indications such as uncomplicated
The number of candidates in African field trials will P. falciparum in pregnancy or Intermittent Preventive
increase significantly, reflecting the higher proportion of Therapy (IPT) in either infants or pregnant women
blood-stage candidates in development and the overall (azithromycin-chloroquine). Not in paediatric formulation
increase in candidates 6 preclinical candidates being developed for treatment of
The number of vaccine projects in clinical trials is likely to uncomplicated P. falciparum malaria (isoquine, PS-26,
continue to increase over the next few years and stay at tetracyclines, trioxanes, 4(1H)-pyridone GSK 932121 and
relatively high levels for the foreseeable future SAR9726A/T3) - these are all non-artemisinins
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2 preclinical candidates being developed for treatment of This is because today’s
P. vivax (tinidazole-primaquine and tafenoquine). portfolio superimposes a
current peak of ready-to-
It is important to note that these first-line indications do not Today’s drug register products on top of
represent the whole story since, once registered, product portfolio is the normal funnel-shaped
developers are likely to trial and register some or many of unlike any that drug pipeline. This peak,
these drugs for additional indications e.g. uncomplicated policy-makers seen at phase III in Figure 12,
malaria in pregnancy and/or IPT in infants or pregnant
women. This cannot be predicted, however, as it is up to
have seen in is composed of new
developers which, if any, additional indications they will seek.

the past, or are combinations or formulations
likely to see of anti-malarials that are
This portfolio is unlike any that policy-makers or drug devel- in the future already on the market. These
opers have seen in the past or are likely to see in the products have little or no
foreseeable future. As noted above, an ideal product attrition, as most are based
portfolio is funnel shaped, with a large number of preclinical on existing therapies i.e.
projects being whittled away by attrition until only one or two virtually all will successfully complete phase III trials to
products reach the market, and are therefore available to registration and subsequently move to phase IV trials aimed
policy-makers to consider purchasing, distributing or using. at optimising and assessing their use. Behind this phase III
However, today’s malaria drug portfolio is the reverse of this, peak is the traditional funnel-shaped pipeline of truly novel
with twice as many products in registration and clinical trials anti-malarials, consisting of New Chemical Entities (NCEs)
as there are in preclinical. that have been developed from scratch and will be subject to
Figure 12. Global malaria drug portfolio in December 2006 (n=21)
* A “breakthrough innovation NCE” is a novel candidate that targets malaria in a completely new way. An “NCE in a known class” is a novel candidate,
but with a non-novel method of action i.e. it is an addition to an existing class of drugs. “Other” includes Fixed Dose Combinations, label extensions,
reformulations and re-registration of existing drugs to Western standards
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the harsh scientific laws of pharmaceutical attrition. As is the 1.2.1 THE DRUG DEVELOPMENT PATHWAY
case with all drug development, only a minority of these
The pathway to licensure
novel projects will reach large-stage trials and an even smaller
number will exit as successfully registered drugs. The most expensive and central part of a drug’s clinical devel-
opment is the journey to registration. All the drug products
This “two-peak pattern” is a one-off anomaly that reflects
listed above will follow a similar development plan, as seen in
the recent history of malaria product development; in partic-
Figure 14 (see Annexe 3a for full Clinical Development Plan).
ular, an early 2000s policy shift to artemisinin combination
Overall, this pathway is well-travelled, well understood and
therapies (ACTs) as the global standard treatment for malaria,
fairly straightforward.
and the advent of Product Development Partnerships (PDPs)
that combine industrial and public sector skills to develop The recent WHO recommendation in favour of combination
new drugs. antimalarials over monotherapies, has increased development
time and cost for new anti-malarial drugs. As Figure 14 shows,
These PDPs, including the Medicines for Malaria Venture
the advent of combination therapies means developers must
(MMV) and to a lesser extent the Drugs for Neglected Diseases
first test the component drugs in isolation, before combining
Initiative (DNDi) XV, now represent nearly half of the global
them and starting the phase I to III process again. This
malaria drug development portfolio (see Figure 13). Therefore
increases clinical development time from around 5 years to
their decision to focus on quick-to-develop ACTs in the short-
6-7 years and adds complexity, and therefore cost, to the
term, while building longer-term portfolios in the background,
development process. As noted above, while current products
has had a major impact on the malaria drug field. The PDPs
generally combine an NCE with an artemisinin, new products
now have seven products with similar target markets in or
are likely to combine two NCEs; both options are therefore
near to registrationXVI, including five competing ACTs and two
shown.
products for severe malaria. Private sector activity has added to
this total, with sanofi-aventis and Pfizer respectively developing Phase IV trials
a product for severe malaria and a non-ACT combination.
After registration, most new drugs will enter phase IV field
This coincidence of competing new products will pose thorny trials. These are large-scale, and generally less complex trials
issues for policy-makers and funders, as discussed below. that are used to bridge the gap between highly controlled
licensure trials in a few thousand subjects, and largely uncon-
trolled use by millions of patients, many of whom will have
Figure 13. Global malaria drug portfolio in development in coincident diseases or health conditions, and some of whom
December 2006 by lead doer type (n=21) may not even have malaria. A relatively small component of
phase IV will involve small, tightly-controlled trials (e.g. to
measure haematological impacts) that will need to be carried
out at more advanced sites, usually licensure standard sites.
There is broad agreement that a phase IV programme should
include the following trials:
Safety (ideally in the context of formal pharmacovigilance
data collection i.e. via registries)
Effectiveness and comparative efficacy
Treatment interactions
Population level studies (e.g. pharmaco-epidemiological
and resistance studies)
Patient adherence and provider compliance
Cost-effectiveness studies.
However, there is still no agreement on the specifics of how
*SMEs = small to medium enterprises
these trials should be done (e.g. number of enrolments, in
what age groups, at how many centres, which components
need to be done at licensure sites, head-to-head or not), or
even who should be responsible for conducting them. This
XV DNDi is now pulling out of malaria drug development to focus on kinetoplastids

XVI Six of these are from the formal structural PDPs, MMV and DNDi; the seventh is from WHO/TDR in a functional PDP with companies
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Figure 14. Simplified standard phase I-III development plan for malaria combination therapy drugs
* Bioequivalence studies verify that

clinical batches used in trials are the
same as the large-scale production
batches to be sold commercially once
scaled-up manufacturing is in place
The phase I combination trial can also

be run in parallel with the phase IIb
NCE trial to further accelerate progress
partly reflects the global community’s limited experience in with the remainder being “all age” trials that would
conducting phase IV trials of new products for developing inevitably also include large numbers of infants and children.
world diseases (which in turn reflects the paucity of new These numbers are in the mid-range between the 5,000-
treatments in the decades prior to 2000). The only formal 10,000 enrolments noted in early discussions with MMV staff
phase IV programmes to support introduction of new (encompassing smaller trials covering safety, efficacy, compli-
products have been rectal artesunate for malaria; planned ance and adherence only) and the 30,000 enrolments
(but cancelled) Lapdap trials for malaria; and miltefosine trials envisioned in the Lang model11. The Lapdap programme did
in India, Bangladesh and Nepal for visceral leishmaniasis. All not stipulate how long it might take to reach these numbers,
these have been co-ordinated by WHO/TDR but none have while the Lang model envisaged rolling phase IV enrolments
yet reached completion. There have also been scattered over a 4-5 year period.
Coartem post-registration trials conducted outside a formal
The Lapdap programme has to be treated with caution for
phase IV programme.XVII
several reasons. Proposed enrolments were based on head-
In recent years, some work has been done to codify the to-head trials between a new product and existing products,
possible structure of a phase IV programme, including three rather than new products being tested against each other or
proposed or discussed approaches (doubtless, more exist). in three-way trials against an existing drug. This reflected
These include a generic phase IV model developed by Lang WHO/TDRs preferred approach, while some also believed that
and WHO/TDR colleagues11; an approach noted in early dis- product developers establishing a foothold in the market
cussions with MMV staff; and the Lapdap regime, developed would be reluctant to allow their new product to be trialled
by WHO/TDR in conjunction with GSK, and which is effective- directly against a new competitor drug. We note, however,
ly a scaled-down version of the Lang model.11 The Lapdap that the 3-arm direct comparison approach is already being
programme is discussed here as an example of what phase IV used in EDCTP-funded ACT comparator trials. It is also the
might look like. preferred approach proposed by the ACT Consortium; and
has been discussed by MMV. Direct comparator approaches,
The Lapdap phase IV programme envisioned multi-centre
as proposed by these groups, require significantly lower
trials enrolling around 23,000 patients in a range of studies
patient numbers. The Lapdap programme approach may also
including pharmaco-vigilance and safety, effectiveness and
be superseded by new proposals, for instance, the proposed
comparative efficacy, compliance and adherence, and resist-
Phase IV Consortium recently discussed newer and much
ance studies, but it did not include cost-effectiveness studies.
larger figures.
Around half the planned trials were in the under-5 age group,
XVII To a degree, information can also be drawn from a range of analogous trials, including the large-scale and efficient IPTi Consortium trials, IPTp studies, and various
comparator trials of existing and new anti-malarials (e.g. chloroquine, S-P, and AS/AQ).
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Label extension trials Not all MMV drugs would go through this process, since
good results for the first two or three drugs would remove
In addition to the licensure trials required for all products and
the need to trial all follow-on products for these specialised
the phase IV trials that most products will undergo, some
indications.
newly registered drugs will also embark on label extension
trials i.e. trials designed to extend a product’s use. For 1.2.2 THE DRUG FUTURE
example:
Feeding the current two-peak anti-malarial drug portfolio
Extending the primary treatment indication to new patient through the standard development pathway, and applying the
groups e.g. treatment of uncomplicated malaria in expected forces of attritionXVIII, provides us with a picture of
pregnant women, patients with HIV coinfection or patients likely future resource demands for malaria drug development.
with sickle-cell anaemia
We have developed two projections to reflect possible policy
Developing a new treatment indication e.g. use in
and funding changes now being discussed. The first scenario
Intermittent Preventative Treatment for infants or pregnant
is closer to an extrapolation of the R&D situation over the
women (IPTi and IPTp), follow-on treatment for severe
past 5 years, where development of new drugs was limited by
malaria, or treatment of P. vivax.
donor funding; in the case of MMV, this led to an initial goal
Unlike phase IV trials, label extensions are formal trials of registering one new product every five years. Under this
following regulatory guidelines at licensure standard sites. scenario, only two new products enter clinical trials each year.
They differ from informal trials aimed at testing a product in
The second scenario reflects a recent push for more products
new groups, since the latter cannot necessarily be used to
covering more indications, and a willingness to back this up
support a new regulatory approval.
with funding. For instance, MMV is now being asked to
It is also important to note that label extension trials are an consider registering two or even more new products every
option, not a requirement i.e. a product developer may or 5 years and will likely expand their preclinical portfolio by
may not choose to pursue a label extension. This explains the picking up more projects from Calls for Proposals and by
paucity of drugs indicated for use in pregnant women and actively fostering back-up compounds. For example, MMV
HIV+ patients, since private companies have traditionally and the Wellcome Trust are working in collaboration with the
been reluctant to trial their products in these higher-risk, Novartis Institute for Tropical Diseases and the Singapore
higher-liability groups. Economic Development Board to develop new leads; while
the NIH and sanofi-aventis also have in-house malaria
Although every group is likely to pursue a different set of
programmes. While some of these product developers will
label extensions - or even no extensions at all - for information
develop drugs to their own timetable, others are working
purposes, we have included a sample MMV label extension
with a view to subsequent collaboration with MMV. Under
programme below. These would begin once phase III trials for
this second scenario, the preclinical feed is therefore doubled,
the first indication (uncomplicated malaria) were complete,
with four new products entering clinical trials each year.
and would take place while registration for this indication
was underway:
A treatment trial for uncomplicated malaria in around 400
pregnant women, followed for up to 2 years (i.e. through-
out pregnancy and until the baby is one year old)
A phase I drug interaction study in around 60 HIV
co-infected patients, to ensure the drug’s absorption,
distribution, metabolism and excretion are unaffected.
Once pharmacokinetic, safety and efficacy data are available
from the pregnancy trial, work could begin on a new
indication:
Trialling the drug for IPT in pregnant women, although the
methodology and approach are still under discussion (IPTi
trials are also only at the discussion stage).
XVIII See Annexe 2 on Methodology for attrition rates used

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Figure 15A. Scenario One: Projected malaria drug portfolio to Figure 15B. Scenario Two: Projected malaria drug portfolio to
2012 with a feed of 2 new clinical candidates per year 2012 with a feed of 4 new clinical candidates per year
The future drug portfolio the development pipeline per decade. By contrast, if policy
and funder interest continues to increase, as under scenario
Figure 15 illustrates the likely number of projects generated
two, this lull will be filled with new projects feeding in from
by the two scenarios described above over the five-year
preclinical, and project numbers are likely to be sustained for
period to 2012.
the foreseeable future as new leads replace the previous ACTs
Two issues are worth highlighting. The first is that phase IV (see Figure 15B).
trial projections are the same under both scenarios; this is
This is a choice for policy-makers in the West and in develop-
because changes early in the development process will not
ing countries, and will reflect their funding capacity, their
have worked their way through to the phase IV stage by
expectations of resistance and demand, and the ability of
2012. Phase IV demand is only affected by drugs that will be
developing country health systems to absorb new treatments
registered in the next few years, and in particular by the ACT
and treatment protocols, particularly in the public sector.
peak identified above. This ACT peak means that policy-
Nevertheless, as the second scenario seems more likely going
makers will face an unprecedented level of phase IV demand
forward, this forms the basis of trial and resource modelling
under either scenario, with a possible twelve drugs in phase
for the remainder of this report.
IV trials by 2010 or 2011, each needing to enrol tens of
thousands of patients. The future drug trial burden
The second issue to highlight is the catalytic role of preclini- As with vaccines, these project numbers need to be translat-
cal activity. Under scenario one, where preclinical R&D ed into trial demand if we are to have a more accurate picture
continues at levels similar to that of the past five years, we of upcoming resource needs. This trial demand is broken
see a sharp drop in clinical projects as developers reach the down into licensure and phase IV trials, since these are so
end of the ACT wave, followed by a lull of several years as the different in terms of resource needs, enrolment size, and trial
early portfolio matures (see Figure 15A). Once mature, we site requirements as to require separate analysis.
would then see perhaps 1-2 new anti-malarial drugs exiting
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Licensure trials XIX Figure 16. Projected malaria drug licensure trials by year
(at standard attrition rates - under Scenario Two)
Although project numbers remain steady under Scenario
Two, it is important to note that this does not translate into
an even distribution of trials over time. This is because the
current peak of late-stage projects in large trials will be
gradually replaced by a feed of new projects in smaller early-
stage trials, with equilibrium probably not being reached until
well after 2012.
As a result, large scale drug trials should generally phase out
after 2009, with demand focussed instead on small and
medium-sized field trials; with perhaps 12 to 14 trials of less
than 300 subjects in most years (see Figure 16).
Phase IV trials
By contrast, phase IV trials will be imminently needed for the
seven drug products already in or beyond phase III, while an
additional four drugs are likely to reach phase IV trials by
2012XX. The imminent phase IV candidates are:
CDA, DHA piperaquine and Coartem Dispersible which
are due to be registered in 2008, and Pyramax in 2009 (all
MMV)
AS/AQ and AS/MQ, both registered in 2007 (DNDi)
Intrarectal quinine (sanofi-aventis).
Policy-makers
Table 4. Projected number of phase IV trials over 5 years based on the Lapdap programme are now facing
NUMBER OF NEW TRIALS/YEAR
unprecedented
NEW PHASE IV TRIALS DURATION
(years) Year 1 Year 2 Year 3 Year 4 Year 5
phase IV trial
IEC* stage I 2 3 4 1 3 1
demand
Observational (Pharmacovigilance) 5 3 4 1 3 1
Safety and Effectiveness 4 3 4 1 3 1
TOTALS PER YEAR 15 20 5 15 5
* Information, Education and Communication
As there is no agreed phase IV approach, we used the Lapdap

programme to provide sample phase IV trial projections (see
Table 4). We emphasise, however, that more or less ambitious
phase IV programmes will deliver very different figures (see
discussion on page 29). Nevertheless, this represents an
unprecedented level of demand for large-scale phase IV trials.
XIX Although label extension trials are also licensure trials, they are not included in our modelling simply because there is no way of knowing which product developers will
choose which label extension trials for which products; indeed, many products will never undergo label extension trials
XX Registration of RTS,S in or near 2012 will dramatically increase phase IV trial demand, but the timeframe is outside the scope of this project
R E S O U R C E I M P L I C AT I O N S > T H E M A L A R I A P R O D U C T P I P E L I N E 33
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IMPLICATIONS
As we saw in Section 1, funders and policy-makers now face a difficult and changing
landscape in terms of increased delivery of malaria products and the increased trials
needed to support these. This section converts these product and trial projections into
estimated resource demands over the five-year period to 2012, in an effort to provide
decision-makers with the tools to navigate this landscape. Demand projections include
both the cost of progressing products through the pipeline, and estimated demand for
trial sites where these products can be tested.
2.1 DEVELOPMENT COSTS 2.1.1 COST OF CLINICAL DEVELOPMENT OF

THE VACCINE PORTFOLIO
The cost of developing new malaria products in clinical trials
has been broken down into two categories: Empirical malaria vaccine trial costs were obtained from
various product developers for a range of Western and
Clinical development costs, defined as direct costs relating African trial sites, as shown in Table 5. Costs were obtained
to clinical trials, including per patient trial costs and central from University of Oxford, MVI, WRAIR, NMRC, MVDB,
trial management costs Institut Pasteur, University of Maryland, WHO/IVR, and EMVI;
Manufacturing cost of the trial product, including the and include trials conducted in the United States, the United
process development, toxicology, stability, vialling and Kingdom, Germany, Holland, Switzerland, China, Gabon,
batch manufacture needed before a product is approved Tanzania, Ghana, Kenya, Mozambique, Mali and Burkina Faso.
for testing in humans. While not a direct clinical trial cost,
these costs are nevertheless an intrinsic part of the overall
development package and are therefore included as a
guide for policy-makers and funders.
It is important to note that our estimates are of total cost, and
that some of these costs will have already been partially
covered by forward donor commitments. These commit-
ments are sometimes known, for example the large Bill &
Melinda Gates Foundation contribution for the development
of RTS,S, and are therefore noted against our cost estimates.
In other cases, only donors are aware of what they have
committed for the years ahead. In these cases, the size of the
funding gap can only be known if donors collectively disclose
their forward commitments, which can then be offset against
the cost estimates below.
We have not included overheads, institutional costs or other
indirect costs since these vary greatly between institutions,
PDPs and private groups and often cannot be readily verified.
This means the development and manufacturing costs below
represent the total direct funding needed for clinical develop-
ment of new malaria products, rather than the total cost of
maintaining the product development pipeline.
34 R E S O U R C E I M P L I C AT I O N S > T H E M A L A R I A P R O D U C T P I P E L I N E
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Table 5. Empirical clinical development costs for malaria vaccines
TOTAL COST (US$) NUMBER OF FIELD COST PER

SUBJECTS SUBJECT (US$)*
Phase Ia
228,880 36 6,358
463,188 60 7,720
173,454 20 8,673
611,939 60 10,199
336,737 30 11,225
997,365 70 14,248
883,209 60 14,720
506,700 30 16,890
620,690 30 20,690
Phase Ia/IIa
521,361 48 10,862
367,955 30 12,265
468,435 35 13,384
553,257 40 13,831
1,569,247 104 15,089
1,317,944 75 17,573
TOTAL COST (US$) NUMBER OF FIELD COST PER TOTAL FIELD TOTAL ESTIMATED
SUBJECTS SUBJECT (US$)* COST (US$) CENTRALISED COST (US$)
Phase Ib
926,870 36 9,913 356,870 570,000
1,677,558 100 11,077 1,107,688 569,870 **
1,028,224 30 15,274 458,224 570,000

1,229,526 40 19,732 789,284 440,242 **
Phase IIb
1,700,070 400 2,524 1,009,675 690,395 **
1,958,673 450 2,730 1,228,673 730,000

2,448,155 450 3,818 1,718,155 730,000
2,253,256 340 4,480 1,523,256 730,000
1,648,913 180 5,105 918,913 730,000
2,110,433 270 5,113 1,380,433 730,000
2,358,421 270 6,031 1,628,421 730,000
Estimated Phase III
85-95 million? 15,000 4,350 20-30 million?
All cost have been adjusted for inflation and presented in US$2600
* All costs are centralised
** Figures reflect actual centralised costs
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In summary, these data suggest that: Figure 17. Projected outstanding vaccine trial cost applying
mid-range portfolio attrition rates
Phase Ia Western safety trials with 30-70 volunteers cost
around US$0.4 million to US$1 million
Phase Ia/IIa combined safety-challenge tests in ~50-75
Western volunteers cost up to US$1.25 million
Phase Ib safety tests in Africa with around 100 patients
cost up to US$1.7 millionXXI
Phase IIb trials in Africa with around 400 patients cost up
to US$2 million - US$2.5 million.
Phase III trial costs are estimates rather than hard figures for
several reasons. The only vaccine candidate that is likely to
reach phase III trials before 2012 is RTS,S, which has its own
special set of funding circumstances. In particular, RTS,S
phase III trials have already been advance-funded through
GSK Biologicals and a US$107 million grant from the Bill &
Melinda Gates Foundation via PATH-MVI in 2005. This
advance grant was projected to cover phase II and III clinical
development costs.XXII We note however, that the original
grant may no longer be sufficient to cover all costs due to
upward pressure on the phase III programme (and therefore
on costs) stemming from potentially slower enrolment at trial
Just over 60% of this projected funding is likely to go towards
sites and lower malaria rates due to interventions such as
African field trials, or around US$122 million to US$146
bednets and indoor residual spraying. This may necessitate
million if RTS,S trial spend is included. This represents a sub-
top up funding. Despite this, we have included rough
stantial funding injection for the “trial business” in Africa,
estimates for the cost of a multicentre phase III trial for the
which is the main (and sometimes only) source of revenue for
sake of completeness. These are based on extrapolations of
many African field sites, particularly young sites.
phase IIb per patient trial costs and informed guesstimates of
central costs.
Extrapolating funding demand forward over a five-year
period for the current clinical and preclinical vaccine portfolio
suggests that:
Total cost (without offsetting forward funding already
given to RTS,S) over the next five years for the global
vaccine portfolio, using a mid-range attrition rate, would Over 60% of
be in the range of US$208 million to US$227 million
(adjusted figure of US$224 million to US$247 million)
vaccine trial
Once forward funding for RTS,S is taken into account, total
funding will
outstanding cost is around US$101 million to US$120 million go to African
(adjusted figure of US$117 million to US$140 million). (See trial sites
Figure 17)
Application of likely highest and lowest attrition rates gives
a total estimated outstanding cost of US$88 million -
US$126 million (adjusted figure of US$103 million -
US$148 million).
If RTS,S costs continue to increase, as noted above, total cost
may be somewhat higher.
XXI Phase Ib/IIb data was excluded due to insufficient data

XXII The grant did not cover the first phase II pivotal trial in infants (Mozambique) which was covered by a previous grant in 2001
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2.1.2 COST OF CLINICAL DEVELOPMENT Extrapolating these typical clinical development costs forward
OF THE DRUG PORTFOLIO over a five-year period for the current drug portfolio suggests
that clinical drug development will cost in the range of US
Clinical development costs for a typical malaria drug, based $217 million to US$257 million (adjusted figures of US$249
on empirical ranges from product developers such as MMV million to US$295 million) to 2012.XXIII We note that this total
are listed in Table 6. For the sake of completeness, these cost will likely be partially offset by donor funding commit-
figures include the cost of all trials, including trials conducted ments for 2007 / 08, although these are not publicly
in Asia, although our focus is primarily on African needs. available.
The majority of funds to meet these costs will come from
Table 6. Typical clinical development costs for a fixed dose public donors, although private pharmaceutical companies
combination (FDC) malaria drug* will also contribute. The private contribution is, however, not
expected to be substantial since most companies seek public
PHASE# NUMBER TRIAL COST PHASE COST partnering or support for later-stage clinical development of
OF TRIALS (US$) (US$)
their products, which is where the bulk of costs are incurred
Phase I NCE 1 1,166,480 1,166,480
(e.g. Jomaa Pharmaka’s fosmidomycin-clindamycin may do
Phase II NCE 3 898,800 3,811,920
so XXIV).
898,800
2,014,320 These cost estimates include drugs for both P. falciparum and
Phase I FDC 1 1,166,480 1,166,480 P. vivax, and are based on a feed of four new candidates per
Phase II FDC 2 2,014,320 2,913,120 year entering clinical trials, as discussed above. (A feed of two
898,800 new clinical projects per year would give a 15% cost
Phase III FDC 2 7,351,680 14,703,360 reduction to an estimated US$187 million to US$216 million
Phase I bioequivalence 1 1,166,480 1,166,480 (unadjusted) total clinical development cost). They also
Registration -- 300,000 300,000 assume that, once drugs currently in the clinical pipeline have
TOTAL CLINICAL DEVELOPMENT COST (NCE PLUS ACT) 25,227,840 finished development, all new projects will be developed as
TOTAL CLINICAL DEVELOPMENT COST (TWO NCES) 30,206,240 more expensive combinations of two new drugs (i.e. two
NCEs) rather than as combinations of an NCE with an existing
* Clinical costs are those directly associated with the clinical trial. They do not artemisinin derivative. These collective assumptions are
include other costs linked to the clinical development of a product such as designed to reflect current changes in policy and develop-
overheads, manufacturing, or toxicology
All costs have been adjusted for inflation and presented in US$ 2006 ment practice which, if continued, seem likely to lead to
# See clinical drug development plan (Annexe 3a) for further details on trial design increased drug R&D activity across the board. Finally, figures
do not include costs for phase IV or label extension trials,
In some cases, MMV may include an allocation for “partner since these are currently undecided and unquantifiable.
costs”, which could add an average additional 15.5% to the
total development costs in Table 6. These are costs incurred
by the development partner (e.g. a developing country phar-
maceutical firm) to manage their end of the process, in
particular manufacturing and scale-up. We have not,
however, included this in our average clinical development
cost for two reasons. Firstly, partner costs are presumably not
incurred (or to a far lesser extent) when the partner firm is a
large experienced Western drug company such as GSK or
Novartis; secondly, partner costs are not seen in the majority
of drug development projects by other groups. This is not a
criticism, simply an observation: This approach may cost
more, but it is a cost MMV is willing to bear in order to
involve more companies from developing countries, while still
moving projects forward quickly and with a high degree of
quality control.
XXIII Including process development, toxicology and stability studies, vialling, and batch manufacture
XXIV Public sponsors may decide to continue or subsidise this project after the collapse of Jomaa Pharmaka, the small company developing fosmidomycin-clindamycin
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2.2 MANUFACTURING DEMAND or lyophilized; if consistency batches are included; and if
toxicology studies are for products formulated with commer-
2.2.1 VACCINE MANUFACTURING COSTS cially available adjuvants or with novel proprietary adjuvants
(which require more extensive testing).
We examined the costs involved in the manufacture and scale-
up of a stable malaria vaccine suitable for use in humans. Despite these variables, the data nevertheless suggest that
Empirical preclinical manufacturing costs associated with the total cost to develop and manufacture one recombinant
process development, formulation, and release of a number of malaria vaccine formulated with two different adjuvants in
malaria vaccines were obtained from a range of product quantities sufficient to support phase I and phase II clinical
developers including EMVI, MVI, WRAIR, MVDB, University of trials is around US$2.5 million.
Oxford, Institut Pasteur and the University of Lausanne. Table
Additional costs associated with feasibility studies, assay
7 lists the preclinical development costs obtained for a number
development, and Investigational New Drug (IND) preparation
of recombinant proteins, the most common vaccine develop-
and submission would increase the preclinical development
ment platform in the malaria vaccine portfolio today. These
costs to around US$4 to US$5 million per candidate; while
manufacturing costs are representative of a range of produc-
use of other technologies (e.g. synthetic peptides) may prove
tion facilities located in the US, Europe, Australia, India, and
cheaper.12
China, and include both public and private facilities.
By extrapolating these costs forward over a five-year period
The figures listed in Table 7 vary according to a variety of
to 2012, we estimate that at least US$72 million (adjusted
factors, including: the complexity and stability of the antigen
figure of US$80.7 million) would be needed to cover manu-
to be developed; whether adjuvant selection and formulation
facturing for the current global vaccine portfolio.XXV
development are included; if the final sterile bulk is stored
Table 7. Empirical preclinical manufacturing costs of recombinant malaria vaccines candidates*
TOTAL COST PER Number of Process Formulation Stability and Toxicology GMP batch Scale-up Number of
CANDIDATE (US$) vials filled development and vialling potency description volume (L) formulations
(US$) (US$) (US$) (US$) (mg/L) developed
466,560 2000 294,192 9,072 77,760 85,536 5 20 1

673,272 4000 458,784 25,272 103,680 85,536 25 20 1
1,349,1261 2000 405,000 44,000 569,000 331,126 25 30 2
1,365,018 2000 812,274 32,400 114,048 406,296 16 50 1 ^
1,425,600 -- 907,200 129,600 194,400 194,400 -- -- --
2,082,150 2000 667,150 915,000 ** 500,000 10 10 2
2,309,175 10000 1,059,175 750,000 ** 500,000 10 100 2
2,309,175 10000 1,059,175 750,000 ** 500,000 10 100 2
2,411,709 2000 1,678,947 250,000 214,000 268,762 10 100 1
2,501,824 10000 2,315,344 *** 100,000 86,480 200 100 1
5,294,6152 10000 3,496,135 1,298,480 ** 500,000 6 50 2
283,1253 1000 -- 77,760 55,728 149,637 -- -- 1
* From lab-scale industrial production to a scaled-up certified manufacturing process; including, generation of purified bulk, quality control sufficient to support a phase I
clinical trial, formulation & vialling sufficient for one GMP clinical batch, real time and accelerated stability studies for a minimum 6 months and maximum 2 years, and
toxicology testing in rodents. All figures are inclusive of actual and budgeted costs
Assay development costs and IND preparation and submission costs are not included
** Costs for stability and potency testing included in the formulation & vialling costs
*** Costs for formulation & vialling included in the process development costs
^ Toxicology testing for two formulations
-- Details not provided
All costs have been adjusted for inflation and presented in US$ 2006
1. Personnel costs not included
2. Process development of two antigens
3. Costs are for the re-formulation and release of a clinical batch sterile bulk
(i.e. no process development cost)
XXV This assumes that the preclinical phase will be refilled at a steady rate of 5 projects per year
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Vaccines developed in the public domain will ultimately Estimated additional costs for a candidate malaria drug are
require collaboration with industry to deliver the final listed in Table 8. About US$5 million is needed to manufac-
product. Ideally, a large-scale manufacturing facility that ture a sufficient quantity of API (active pharmaceutical
prepares phase III material would then be used for the vaccine ingredient) to support clinical trials of a combination drug
manufacture post-licensure. However, only one vaccine (NCE plus an artemisinin derivative); while toxicology tests
candidate (RTS,S) will require significant production capabili- double this figure to around US$10.5 million per drug. We
ties over the five-year period to 2012 and, for now, this has note that manufacturing and toxicology costs for a drug
been addressed by investments already made by GSK (as prior candidate are higher if it combines two NCEs rather than an
investments, these do not form part of forward manufactur- NCE + artemisinin derivative, due to the additional manufac-
ing cost estimates). GSKs investment was for construction of turing and toxicology steps required to support development
a manufacturing plant with capacity to cover production of the additional novel partner drug. Total manufacturing and
needs for phase III trials, phase IV trials, and initial post- toxicology costs under this approach increase to US$14.4
licensure supply. This means there is no immediate unmet million per drug.
demand for large-scale vaccine product manufacture to
Extrapolating these costs forward over a five-year period to
advance the global vaccine portfolio.
2012, and taking into account the likely mix of new ACTs and
2.2.2 DRUG MANUFACTURING COSTS novel combinations, we estimate that manufacturing and
toxicology costs for the global drug portfolio will be around
In addition to the direct clinical costs associated with develop-
US$184 million (adjusted figure of US$210.3 million), based
ing a malaria drug, product developers must provide funds to
on a preclinical feed of four new candidates per yearXXVI.
manufacture sufficient quantity of drug to support the clinical
development process from IND submission through to phase
III. Furthermore, developers must continue to fund non-
human studies alongside the clinical phase so as to optimise
their knowledge and understanding of the safety of the new
drug candidate (e.g. reproductive and liver toxicology tests;
and genotoxicity and carcinogenicity studies). While not part
of direct clinical trial costs, these costs are nevertheless an
important underpinning for the clinical development process.
Table 8. Manufacturing and toxicology costs for a candidate malaria drug
ACTIVITY AVERAGE COST (US$)

Manufacture of API
TOTAL Manufacturing costs (NCE + artemisinin derivative) 5,050,000
TOTAL Manufacturing costs (NCE + NCE) 6,500,000
Toxicology
TOTAL Toxicology costs (NCE + artemisinin derivative) 5,562,500
TOTAL Toxicology costs (NCE + NCE) 7,937,500
Total additional development costs (NCE + artemisinin derivative) 10,612,500
Total additional development costs (NCE + NCE) 14,437,500
API = Active Pharmaceutical Ingredient; NCE = New Chemical Entity

All costs have been adjusted for inflation and presented in US$ 2006
XXVI It assumes that, once drugs currently in the clinical pipeline have finished development, all new projects will be developed as combinations of two new drugs
(i.e. two NCEs) rather than as combinations of an NCE with an existing artemisinin derivative
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2.3 TRIAL SITE DEMAND AND ture to support phase IV trials can be relatively modest -
SUPPLY indeed sophisticated upgrades can be counter-productive to
the goal of field-testing a product. Phase IV sites should,
Trial site demand is driven by the number of products moving however, have sufficiently large populations; a good
forward and the number of trials each of these products will Demographic Surveillance System (DSS) to track population
require to support registration and subsequent roll-out. level impact; and the ability to conduct large-scale interven-
However, behind this broad-brush picture are a plethora of tional trials. Unlike licensure trial demand, phase IV demand
practical distinctions that are the true determinants of trial is not segmented, since phase IV trials deliberately seek to
site demand. Appropriate donor investment decisions require enlist a normal cross-section of the malarial population as
a proper assessment of these distinctions as the basis for they present to the clinic, including infants, children, adults
more accurate estimates of the presence, size, nature and and pregnant women. These less restrictive criteria mean the
timing of trial site capacity gaps. The discussion below supply of phase IV sites is inevitably larger than that of
pertains only to trial sites in Africa. licensure sites, and also more easily matched to phase IV trial
demand.
By far the most important factor in assessing trial site demand
is whether the planned trials are phase IV trials aimed at Any meaningful assessment of trial site demand and supply
supporting transition of a newly registered product into needs to take the above factors into account, including
widespread use, or licensure trials aimed at registering a new whether projected product trials are for challenge, licensure
product or new use. or phase IV; for drugs or vaccines; and in which age group
they will be conducted. Such an analysis is carried out below
Licensure trials to support product registration must be
as the first step to assessing if and where gaps exist between
conducted at sites capable of meeting strict regulatory
current site capacity and the anticipated clinical trial load out
standards. This requires highly trained staff (e.g. staff with
to 2012.
experience in working with standard operating procedures
and a high level of data management skills); facilities such as 2.3.1 WESTERN CHALLENGE SITE CAPACITY
laboratory equipment, inpatient infant beds and IT infrastruc-
Artificial challenge tests for pre-erythrocytic vaccines (techni-
ture including internet or satellite connectivity; and
cally called human sporozoite challenge trials or phase lla
supportive structures such as Institutional Review Boards or
trials) are normally conducted in malaria naïve patients in the
Ethical Review Boards. Even within this relatively small group
West to assess safety and efficacy prior to field trials. Some
of skilled sites, not all will be capable of conducting all types
product developers also use a sporozoite challenge for blood-
of licensure trials, since trial demand is further segmented by
stage candidates, however as its use in this situation is still
both age and product type. For instance, malaria drug trials
disputed, such a challenge does not usually act as a go/ no go
predominantly require sites capable of small trials, and which
criteria in moving blood-stage candidates into field trials.
have access to modest numbers of adults and children.
Malaria vaccine trials, on the other hand, initially need small Based on our projections, and using mid-range portfolio
safety and/or challenge trials in adults, then large safety and attrition rates, we estimate a maximum cumulative demand
preliminary efficacy trials in children, and finally the ability to of 23 challenge trials in the five years to 2012, with a
access and manage very large numbers of infants - the target maximum of 10 trials in any given year, assuming that blood-
population for vaccination. The key factors that determine a stage vaccine candidates based on AMA-1 and MSP-1 also go
site’s ability to match these demands are its technical capacity, to challenge.
operational capacity and geographic location in terms of
Challenge trials have very specific requirements including: an
overall site distribution.
insectary to produce infected mosquitoes; a facility to
Phase IV trials present a quite different picture. As the administer the challenge test to patients; and a clinical trial
purpose of phase IV trials is to assess a product’s profile in centre (CTC) to handle vaccination and clinical monitoring.
real-life health systems and populations, most phase IV sites In addition, continued monitoring of patients for several
do not need to be as technically sophisticated as licensure weeks or more either involves subjects being placed under
sites. (We note that a minority of phase IV studies will require continuous observation at a nearby hotel or lodge or requires
a more advanced site e.g. for monitoring haematological subjects to remain in close contact with the clinic (e.g. via
effects). In general, though, laboratory and clinical infrastruc- telephone, or daily or intermittent visits).
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There are five institutions with the capacity to carry out 2.3.2 LICENSURE-STANDARD TRIAL
malaria challenge trials: WRAIR, Imperial College London, SITES IN AFRICA
Nijmegen Medical Centre at Radboud University, NMRC, and
the Center for Vaccine Development (CVD-Maryland) at the 2.3.2 (I) DEMAND FOR LICENSURE TRIAL SITES IN AFRICA
University of Maryland. At each of these institutions, the care All trials for drug and vaccine products seeking registration
of participants is outsourced to nearby CTCs that are inde- must be conducted at licensure-standard sites. (As noted,
pendent of the insectary, although some form a more phase IV programmes may also include a small component at
integrated unit than others. At WRAIR, the insectary and CTC licensure sites but, given their likely small size and uncertain
are located within the same building. Nijmegen Medical nature, these are excluded from our demand projections).
Centre uses the Radboud University CTC located within the
hospital and NMRC transfers its subjects to the Bethesda The likely collective demand on licensure sites in Africa
CTC. University of Oxford undertakes their challenge studies generated by the global malaria drug and vaccine portfolios
at the insectary facility at the Imperial College, London, using going forward to 2012 is seen in Tables 9 to 11 .XXXI These
mosquitoes from either Imperial College or the WRAIR insec- tables translate future product trials into on-the-ground
taries; and CVD-Maryland has an experienced CTC but they enrolment numbers, broken down by age and product type,
source their infective mosquitoes from other facilities (such as in order to give funders and developers a clearer picture of
Sanaria and NMRC).XXVII the likely burden they will face in the next five years. These
enrolment projections are only for African trial sites, as this is
Some of these institutions, such as WRAIR and University of our area of interest (i.e. enrolments in Asia are excluded). For
Oxford, have a great deal of experience, with respectively ease of reading, total mid-point enrolment figures are also
more than 600 experimental infections conducted since 1992 shown graphically in Figure 18.
and 200 experimental infections conducted since 2001. By
comparison, the NMRC has challenged less than 50 subjects These projections suggest that trial site funders, developers
in the past seven years and the CVD-Maryland is now and managers have little to worry about in terms of anticipated
preparing to conduct its first malaria vaccine challenge trial in demand for adult enrolments, with these declining after
more than 10 years. completion of ACT trials in 2008/09 and likely to remain at
less than 3,500 per year thereafter. These are relatively small
Our assessment of these five institutions suggests they can figures to enrol across Africa’s licensure trial network.
each conduct 1-2 challenge trials per year consisting of 25-50
patients per trial (equating to about 340 subjects enrolled in Demand for child enrolments is less smooth, with child drug
challenges per year) XXVIII. Moreover, all of the sites interviewed enrolments phasing down over 2007 to 2009 while child vaccine
indicated they could more than double the number of enrolments start to rise rapidly after 2008: this is likely to make
challenge trials they conduct (to an estimated 715 patient 2009 a peak demand year for child enrolments. A further factor
challenges per year), as long as personnel and clinical costs is that the majority of child vaccine enrolments will be in phase
were provided. This doubling of capacity is contingent on the IIb trials, which generally enrol all patients at one site (usually
completion of facility upgrades under consideration at around 400-800 subjects, but sometimes up to thousands),
Imperial College London XXIX and Nijmegen Medical Centre.XXX and follow these patients for 2 or more years. This means child
In our view, this capacity is more than enough to cater for the enrolments will need to be carefully managed, as they cannot
number of challenge trials projected to occur in the five years simply be spread across all available sites, but must be allocated
to 2012 (with estimated demand probably around five trials to sites capable of handling large-scale vaccine trials.
per year, and unlikely to exceed ten trials per year). The largest hurdle, however, will be short-term infant enrol-
Some institutions that conduct challenge trials do so to ments for RTS,S vaccine trials, which are creating
preferentially assess their own malaria vaccine candidates or unprecedented peak demand for vaccine licensure sites
have their own research agendas. As such, not all product capable of large-scale infant enrolments in 2008 to 2010.
developers with a candidate malaria vaccine may have access This level of demand is unlikely to be repeated again before
to a challenge site or to infective sporozoites; although 2012 since no other candidate is likely to reach phase III
Sanaria’s work to develop large standardised batches of before then. This means trial sites are likely to face very high
frozen sporozoites could solve the latter problem. Thus, our immediate demand for infant enrolments for malaria vaccine
overall assessment that there is sufficient supply of malaria trials, followed by a lull of several years or more before a
challenge sites is contingent on most or all sites being willing second demand peak eventuates.
to subcontract out their services.
XXVII The insectary at CVD-Maryland houses mosquitoes for experimental purposes only
XXVIII This assessment is based on interviews with each of these sites, plus empirical analysis of published and unpublished challenge trials
XXIX Imperial College London is planning to invest £1.7 million into expanding the current facility
XXX Nijmegen Medical Centre is in discussions with the Dutch Government to build a new, dedicated clinical unit and upgrade the production centre to increase stability of
cell lines
XXXI Enrolments for label extension trials are NOT included in these projections, as it is still unclear what trials will be done and in which patient groups
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Table 9. Projected malaria vaccine trial enrolments in Africa to 2012
VACCINE TRIAL ENROLMENTS 2007 2008 2009 2010 2011
ADULTS 200-230 230-310 170-270 200-280 90-140

CHILDREN 250-280 1,040-1,120 2,610-3,520 1,820-3,530 2,520-4,200
INFANTS 900* 7,380* 7,480* 0 60-120
Table 10. Projected malaria drug trial enrolments in Africa to 2012
DRUG TRIAL ENROLMENTS 2007 2008 2009 2010 2011
ADULTS 2,370-4,580 700-1,290 1,670-3,240 1,020-1,740 1,020-1,740

CHILDREN 1,230-3,150 530-1,250 400-1,000 150-300 350-600
Table 11. Projected total malaria drug and vaccine trial enrolments in Africa to 2012
TOTAL ENROLMENTS 2007 2008 2009 2010 2011
ADULTS 2,570-4,810 930-1,600 1,840-3,510 1,220-2,020 1,110-1,880

CHILDREN 1,480-3,430 1,570-2,370 3,010-4,520 1,970-3,830 2,870-4,800
INFANTS 900* 7,380* 7,480* 0 60-120
* These figures are based on clincal development plans for RTS,S as current in Nov 2006
Figure 18. Projected total mid-point enrolment by

year for malaria product licensure trials in Africa Infant
enrolments
for the RTS,S
vaccine will be
the greatest
hurdle for
trial sites
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2.3.2 (II) SUPPLY OF LICENSURE TRIAL SITES IN AFRICA product registration - or at least not without either internal
upgrading or external assistance. Technically competent
As noted above, in order to provide a more accurate assess-
licensure-standard sites tend to fall into two groups:
ment of whether Africa’s licensure trial sites can meet this
demand, we need to examine site capacity from three per- All-purpose sites, which have the capacity to conduct a
spectives: technical capacity, operational capacity and wide range of licensure trials, be these drug or vaccine,
geographical distribution. large or small
Drug sites, which can conduct licensure-standard drug
Technical capacity
trials but may not have the capacity to conduct vaccine
Technical capacity is defined as the on-site skills and physical
licensure trials.
facilities needed to conduct licensure-standard drug or
vaccine trials for regulatory purposes. Sites that do not have Our analysis suggests that at least 23 African clinical trial sites
these skills or facilities may be able to conduct non-licensure will have the technical capacity to conduct licensure-standard
trials, but they cannot be used for trials needed to support malaria product trials by end 2008. This includes 12 “all
Figure 19. African clinical trial sites by technical capacity to conduct licensure malaria product trials
6 MATURE ALL-PURPOSE SITES 5 SITES BEING UPGRADED

1 US Army Medical Research Project-Kenya (USAMRU-K), Kisumu (Kenya) 1 CDC/ KEMRI (Kenya)
2 Wellcome Trust/KEMRI, Kilifi (Kenya) 2 Malaria Research Laboratory (MRL), University of Ibadan (Nigeria)
3 Malaria Research and Training Centre (MRTC), Bancoumana, Bandiagara, 3 Noguchi Memorial Institute for Medical Research Clinical Trials Facility (Ghana)
Doneguebougou (Mali) 4 Service de Parasitologie, University Cheikh Anta Diop, Dakar (Senegal)
4 Centro de Investigação em Saúde da Manhiça (CISM), Manhiça (Mozambique) 5 Niakhar Institut de recherche pour le developpement, Niakhar, Dakar (Senegal)
5 Bagamoyo/Ifakara Health Research & Development Centre (IHRDC), (Tanzania)
6 Medical Research Council (MRC): Basse, Banjul/Fajara, Farafenni (The Gambia)
14 ASSISTED SITES
1 Faculte des Sciences de la Santé, CNHU (Benin)
6 YOUNG ALL-PURPOSE SITES 2 Faso Institute Superior des sciences de la santé, Universite
1 Hospital Albert Schweitzer (HAS): Lambarene, Libreville (Gabon) Polytechnique de Bobo-Diolasso (Burkina Faso)
2 Agogo Clinical Trial Centre, Kumasi Centre for Collaborative Research (KCCR) 3 Institute Pasteur, Abidjan (Cote D'Ivoire)
in partnership with the School of Medical Sciences (SMS), Kumasi (Ghana) 4 School of Public Health, University of Kinshasa
3 Kintampo Health Research Centre (KHRC), Kintampo (Ghana) (Democratic Republic of the Congo)
4 National Institute for Medical Research (NIMR), Tanga (Tanzania) 5 Moi University, Eldoret (Kenya)
5 Navrongo Health Research Centre, Navrongo (Ghana) 6 State Specialist Hospital, Maiduguri, Borno State (Nigeria)
6 Centre National de Recherche et de Formation sur le Paludisme (CNRFP), 7 University of Nigeria Teaching Hospital, Enugu (Nigeria)
Oubritenga/Ouagoudougou (Burkina Faso) 8 Lagos State University Teaching Hospital (Nigeria)
9 Obafemi Awolowo University Teaching Hospital, Ile-Ife (Nigeria)
10 Plateau State Specialist Hospital, Jos, Plateau State (Nigeria)
6 DRUG-ONLY SITES 11 University of Calabar Teaching Hospital, Calabar (Nigeria)
12 Centre De Sante Roi Baudoin, Guediawaye, Dakar (Senegal)
1 Centre de Recherche en Santé de Nouna (CRSN), Nouna (Burkina Faso)
13 Kivunge Public Health Care Centre Zanzibar (Tanzania)
2 Blantyre Malaria Project Research Clinic, Ndirande, Blantyre (Malawi)
14 Médecins Sans Frontières Epicentre, Mbarara (Uganda)
3 QE Hospital Malawi-Liverpool- WellcomeTrust Research
Programme (MLW), (Malawi)
4 Malaria Institute at Macha, Choma (Zambia)
5 Tropical Diseases Research Centre (TDRC), Ndola (Zambia)
6 Komfo Anokye Teaching Hospital (KATH), Kumasi (Ghana)
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purpose” sites currently capable of conducting most licensure cases through MCTA/MVI-funded upgrades linked to large
trials; 6 “drug” sites currently capable of conducting only RTS,S phase IIb trials, which was the first vaccine licensure
drug licensure trials (two being upgraded to vaccine licensure trial for most sites. The exceptions are Navrongo, which
standard by end of 2008); and 5 sites being upgraded to reached capacity through repeat upgrade funding linked to
reach licensure standard by end of 2008 (three to become product trials; and the CNRFP, which has not yet done a IIb
malaria vaccine trial sites; two to become drug trial sites). An vaccine trial, and was upgraded through a capacity strength-
additional 14 sites can conduct licensure-standard drug trials ening grant from AMANET.
with external support, and these represent potential addition-
Four of the six sites are now receiving further MCTA/MVI
al capacity in the future. (See Figure 19)
investment to bring them to full phase III vaccine trial capability
Assignment of sites to these categories was based on trial site in preparation for the RTS,S infant trials.XXXIV
interviews, product developer interviews, expert opinion,
Drug-only sites (drug trials)
audits conducted by others where available (Wellcome Trust,
the TB Alliance, EDCTP) and analysis of licensure experience The six trial sites listed in Figure 19 have each conducted two
at each site. or more drug licensure trials, but none have malaria vaccine
licensure experience. Expert opinion rated these sites as
Mature all-purpose sites (drug and vaccine trials)
“good centres for drugs” or “quite experienced on drug
These six African trial centres are defined as mature sites for trials”. For example, in Burkina Faso, the Centre de Recherche
malaria product licensure trials, and are capable of carrying en Santé de Nouna has conducted 4 malaria drug licensure
out drug or vaccine licensure trials to the highest standard. All trials since 2003, while the Malaria Institute at Macha
are well-established sites with extensive and long-term (> 5 (MIAM), Zambia, has conducted three malaria drug licensure
years) experience in conducting product licensure trials.XXXII All trials and a malaria diagnostics licensure trial in the past 10
sites have conducted a minimum of three vaccine licensure years. Some sites have additional experience in large-scale
trials, including one or more large-scale trials, and all but interventional trials. For instance, the Komfo Anokye
USAMRU-K have run multiple drug licensure trials in parallel. Teaching Hospital (KATH) in Kumasi (Ghana) and the Blantyre
Collectively, these sites have conducted 85% of malaria Malaria Project in Blantyre (Malawi) each enrolled over 4000
vaccine trials in Africa (35 out of 41) and, unsurprisingly, five subjects as part of the Severe Malaria in African Children con-
of the six sites will be used for the large-scale RTS,S phase III sortium study.
vaccine trials commencing in 2008. Expert opinion rated
Three of these sites already have committed funding for
these sites as “state of the art”, “as good as it gets” and
upgrade to malaria vaccine-licensure standard. For instance, a
“excellent”.
grant of €250,000 over two years from AMANET to the
Young all-purpose sites (drug and vaccine trials) Tropical Diseases Research Centre in Ndola (Zambia) to
support an upgrade to conduct relatively small phase Ib or IIb
These six centres have also conducted malaria drug and
vaccine trials; and a grant of nearly US$1.2 million from the
vaccine licensure trials ,XXXIII but all have substantially less
MCTA to the Blantyre Malaria Project Research Clinic to
vaccine experience than the mature sites. Expert opinion rated
upgrade to much larger phase III vaccine trial capability. Other
all these sites as “ready to do big vaccine trials with some
sites are becoming unsuitable for malaria trials. For instance
assistance” or “very good”, although the level of experience
the number of uncomplicated malaria cases at the Malaria
varied within the group. Two sites are particularly experi-
Institute at Macha (Zambia) has dropped more than ten fold
enced: Hospital Albert Schweitzer, Gabon, has over 10 years
from an average of 1,000 cases/year in 2000 - 2003 to 89
experience in drug licensure trials, although only early vaccine
cases in 2005, a development that is impacting on their
experience; and the Navrongo Health Research Centre,
ability to conduct malaria product trials.
Ghana, which has rapidly accrued experience in both drug
and vaccine licensure trials, including trials for meningitis and Sites being upgraded to licensure standards (vaccine
rotavirus vaccines. and drug)
These young sites generally have a background in drug These five sites were assessed by experts as “very close to
licensure trials and/or large-scale GCP interventional trials ready” to take on licensure trials, and most have funding
(e.g. trials for Intermittent Preventive Treatment in Infants, committed to bring them to licensure-standard by end 2008.
insecticide-treated bednet trials and head-to-head drug With the exception of Noguchi, all sites have relevant large-
studies). The move up to vaccine trial capability was in most scale, non-licensure trial experience due to recent IPTi, IPTp or
XXXII The MRTC sites have less than 5 years experience but have been considered as mature based on the number of vaccine trials conducted
XXXIII The Navrongo Health Research Centre has not conducted any malaria vaccine trial but was included in this group as it has conducted several vaccine licensure studies
XXXIV (HAS (Gabon), KCCR/SMS (Ghana), KHRC (Ghana) and NIMR (Tanzania)
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ITN trials. Three of the sites (CDC/KEMRI XXXV, Cheikh Anta trials in the Democratic Republic of Congo and Sudan to
Diop and MRL-Ibadan) have also been involved in a multi- licence new drugs for sleeping sickness and visceral leishma-
centre malaria drug licensure trial in the past, although all niasis. In these cases, National Control Programme sites
require additional investment to be brought fully up to received basic upgrades, including GCP-trained staff and
licensure standards. basic laboratory facilities, with more sophisticated data
management and monitoring being provided centrally. This
Two of these sites are now being funded by the MCTA to fully
allows products to be trialled even in difficult or remote areas.
prepare them for drug licensure trials (Ibadan and Cheikh
Anta Diop); and a further two are being upgraded specifical- Operational capacity
ly for vaccine trials (CDC/KEMRI and Noguchi); Niakhar’s Operational capacity is needed at two levels. The first is the
situation is still unclear. The vaccine upgrades vary in scope general management and financial skills needed to success-
and intention. CDC/KEMRI is being upgraded with fully handle projects (as distinct from technical trial skills). For
MCTA/MVI funding to conduct large phase III infant trials as example, a site capable of managing a licensure-standard
part of the RTS,S program. Noguchi is being upgraded phase II drug trial involving 100 patients followed for 28 days,
through an NIH Malaria Clinical Research and Trial Site may be unable to manage a licensure-standard phase III
Preparation grant as a central hub for administrative matters vaccine trial involving 1,000 patients followed for 2 years;
and high tech work, and initially with the aim of conducting however, they are both licensure-standard sites in the
small vaccine studies (such as phase Ib). technical sense.
Assisted sites (drug) The second is a site’s ability to access sufficient patients to
support efficient trial enrolment. Even technically and man-
These sites can conduct full licensure standard drug trials if
agerially competent sites may experience constraints due to
given appropriate external support. The skills they develop in
limited patient numbers. For example, through “over-use” of
this process also give them a head start on reaching inde-
the resident population by frequent product trials, or due to
pendent licensure-standard due to the increased experience
the increasingly common problem of dropping malaria rates
of the Principal Investigator, GCP training of site staff and
as a consequence of the introduction of bednets and indoor
general site improvements.
residual spraying, which means more subjects are needed to
Drug developers may use assisted sites, in addition to the demonstrate a protective effect. Some sites may also lack
licensure sites listed above, particularly in areas where access to specific patient subsets needed for product trials.
licensure sites are thin on the ground. MMV offers a useful For example, while all trial sites have ready access to adult and
example. MMV’s clinical development programme generally child patients, access to infants may be limited by local birth
uses multiple sites (including some assisted sites), each with rates or by a site’s ability to rapidly access these newborns
relatively small enrolment numbers (100-300 patients) so as through pre-natal clinics and immunisation programmes.
to expedite trials, hedge risk, and increase geographic and
In addition to technical capacity, we therefore also assessed
epidemiological site diversity. Trial management and data
the operational capacity of the 12 “all purpose” licensure
management are centralised, using CROs or Western multi-
sites, in terms of their general management and financial
national pharmaceutical company partners, while more
capacity and their ability to access sufficient patients in each
sophisticated laboratory tests are also done centrally.
age group to support efficient trial enrolment. This analysis
Generally, trial sites work under close central supervision
showed clear differences in operational capacity (and causes
(with fortnightly monitoring), and capacity building focuses
of limited operational capacity) between young and mature
on trial-specific human capacity (GCP training, training in trial
licensure sites. (“Drug sites” were not assessed as, by defini-
protocols, etc.). To some extent, MMV (along with the MCTA)
tion, they are currently only able to conduct drug trials).
does invest in infrastructure upgrades, but their general
approach is to provide modest support to less experienced Mature all purpose sites
sites (e.g. bringing sites online to allow for data collection,
None of the mature sites are constrained by management or
upgrading laboratories, and providing transport infrastruc-
financial incapacity, with all having extensive experience in
ture) rather than attempting to make them fully
handling multiple and often simultaneous licensure trials.
self-sufficient.
Four of these six sites estimated that they had excess opera-
DNDi has used a similar approach to conduct drug licensure tional capacity, with two sites (USAMRU-K and the MRTC)
trials in remote areas and post-conflict states, for example specifically saying they did not have enough projects.
XXXV The related CDC HIV and infectious disease branches are currently preparing for rotavirus, HIV and possibly TB vaccine trials
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USAMRU-K advised that they “always have capacity left tion centres. For instance, the CNRFP site in Burkina Faso
over”, as they leave gaps for potential US army trials which, lacks public water and electricity, which hampers its potential
if unfilled, can be used for trials by other developers; while as a high infant enrolment centre for malaria vaccine trials.
the MRTC linked their excess capacity to their DSS expansion,
These factors tend to place an “operational cap” on the
high malaria rates, and new hospital.
ability of young sites to recruit and manage large-scale infant
However, inadequate patient access and lower malaria rates trials, irrespective of the available infant population. This is
are a looming issue for some. Two of these six sites are not necessarily a negative factor, with some site managers
already seeing slower enrolments in malaria drug trials as the explicitly expressing a preference for managed growth: “if we
local malaria burden is reduced by bednet use or indoor expand too quickly we can breakdown…”; “as a young site,
spraying (CISM-Manhiça and Wellcome Trust/KEMRI Kilifi); it’s better to build up slowly”. However, it does mean that it
while one site additionally cited “trial oversaturation” from may not be prudent to rely too heavily on infant enrolments
recent malaria, pneumococcal, rotavirus and AIDS drug and of 1,000+ per year at young sites to support the RTS,S devel-
vaccine trials in the population. This means longer enrolment opment plan.
times to reach the desired number of malarial patients for
Geographical spread
drug trials; while for vaccine trials, enrolment numbers may
A trial site’s usefulness and relevance in supply terms also
need to increase to allow efficacy to be demonstrated (since
depends on how it relates to the overall distribution of trial
trial size is inversely proportional to malaria incidence).
sites within the framework of trans-African malarial disease
Young all-purpose sites and malaria product introduction. Trial demand cannot be
said to be fully satisfied unless the available trial sites collec-
Young all-purpose licensure sites present almost the opposite
tively represent a reasonable geographic, political, and
picture. While most sites have continuing high malaria
epidemiological cross-section of Africa’s malaria-endemic
incidence and large infant populations, which should make
countries.
them ideal for vaccine trials XXXVI, their enrolment potential is
often constrained in the short-term by limited experience in Drug and vaccine licensure trial sites, both young and mature,
accessing newborns, and by management and financial issues. are well distributed throughout East and West Africa,
including in both Francophone and Anglophone countries
Most young sites feel they have clear limits in terms of sched-
(see Figure 20). However, there are gaps. Central Africa has
uling, staffing, and managing trials. For instance, HAS,
very few trial sites (e.g. there are no trial sites in southern
Gabon estimates that it could recruit and manage two large
Sudan, Angola or Chad). This is perhaps not surprising given
trials but no more (one of these would be the RTS,S phase III
that many of these countries are still in the midst of, or very
trial). Two other sites - KCCR/SMS in Ghana and NIMR Tanga
recently recovering from, lengthy civil and internal conflicts.
in Tanzania - estimate that the planned phase III RTS,S trial
However, there is also a marked absence of vaccine trial sites
will fully occupy them for now, even with the site expansions
in Nigeria, although MMV has a network of drug trial sites
and support linked to such a trial. KHRC in Kintampo, Ghana
there. This gap is potentially problematic from both a political
also estimates that it is at full capacity. These assessments are
and market perspective, given Nigeria’s status as Africa’s most
reinforced by a review of trials at these young sites, which
populous country.
show that, despite large populations, high malaria incidence,
and broad Demographic Surveillance System (DSS) coverage,
most sites have experience of managing hundreds rather
than thousands of patients in licensure trials. The exception is
Navrongo, which has a large patient population, a keen
desire to expand its scope, and proven management capacity
to run multiple trials. For example, it simultaneously
conducted two phase II/III drug trials for Pfizer, a large IPTp
study and a meningitis vaccine trial for GSK. Navrongo is
currently running below full capacity.
A further limiting factor for some young sites was poor local
infrastructure, even allowing for trial-specific upgrades such
as construction or expansion of paediatric wards and vaccina-
XXXVI Some sites had difficulties readily accessing these patients, but this was generally being addressed through RTS,S-linked expansions. For instance, the HAS site in Gabon
and NIMR site inTanzania are currently full, but both are expanding recruitment to additional centres by 2008 using MCTA/MVI funding linked to RTS,S.
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Figure 20. Distribution of malaria drug and vaccine trials sites in Africa
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2.3.2 (III) CAPACITY GAPS This is because the target groups for drug trials are adults and
children, who are both more numerous and more accessible
This overview of African licensure sites shows that there is a
than infants; and because “rolling enrolment” can be used
network of at least 23 sites that should be able to conduct
i.e. enrolment of patients presenting with malaria until the
licensure-standard malaria product trials by end 2008,
target number is reached, rather than a requirement to enrol
including 18 sites already at licensure standard. These supply
in a specific time-window (e.g. within ‘x’ weeks of birth, or to
figures can now be matched against demand projections in
fit in with infant vaccination schedules). These characteristics
order to determine the presence, nature and size of trial site
mean that most licensure sites handle such trials easily, saying
capacity gaps going forward to 2012.
“we just tuck drug trials in alongside our other larger trials”.
Drug site capacity gaps
The availability of drug trial
As seen from the previous forecasts (see Table 10), estimated sites is not an accident, but is
demand for adult and child enrolment in drug licensure trials due to energetic efforts and
peaks from 2007 to 2009 as the current wave of late-stage investment by the MCTA and Child
products comes to an end, and subsequently drops to around MMV to provide sufficient
half these levels. This pattern translates into moderate adult capacity to allow the peak of
enrolments
and child enrolments in drug licensure trials until 2009 “first wave” MMV drug trials
may put a
(around 4,500 for adults and 3,000 per year for children), and to move ahead. More than strain on the
peak enrolments of around 3,000 for adults and 1,000 for half the 18 drug-capable sites site network
children thereafter. The majority of drug trials are likely to be noted above are MCTA sites
small (around 10 trials per year of less than 100 patients) or linked to the development of
medium-size trials (less than 5 per year enrolling around 300 MMVs product portfolio.
patients), which allows them to be distributed across sites
Vaccine site capacity gaps
more easily (see Figure 16).
The situation for vaccine trials is not as straightforward, with
There are currently 18 licensure sites available to meet this
significant divergence in demand between trials in adults,
demand, including the young and mature “all-purpose” sites
children and infants. Adult enrolments in vaccine trials out to
and the drug licensure sites; with additional capacity available
2012 are minimal, peaking at around 300/year. Child enrol-
at the 14 “assisted” sites. Ongoing upgrades will add an
ments are relatively moderate, peaking at just over 4,000 by
additional two sites (Cheikh
2012; but the nature of this demand is somewhat unwieldy
Anta Diop and MRL-Ibadan)
since it mostly consists of a few very large trials concentrated
to this tally by end of 2008.
at a few sites. From 2009 onwards, we anticipate around four
With the exception of the
phase IIb child trials per year, each requiring a site capable of
There is central conflict states, these
large-scale vaccine trials.
no unmet sites are well distributed
demand for throughout Africa’s malaria Infant enrolments associated with phase III RTS,S trials also
zones, including Nigeria. pose potential difficulties. These trials will see very high
malaria drug
demand for enrolment in a patient group that is both smaller
licensure trial In our view, the relatively
(due to birth rate limitations etc.) and more difficult to access
sites moderate enrolments in
than other age groups. Depending on the final design of the
malaria drug trials in the next
RTS,S trials, infant enrolments are likely to be around
3-5 years, and the plethora
7,500/year from mid-2008 through 2010, although declining
of licensure-standard sites
malaria rates due to competing interventions may push enrol-
able to conduct such trials,
ments slightly higher.
means there is no unmet demand for sites to conduct drug
licensure trials nor will there be in the foreseeable future. This As noted above, there are six mature and six young “all
is particularly so as most drug trials are modest in size or, if purpose” licensure sites currently available to meet this
larger, are usually designed as multi-centre trials with a few demand. Measures to bring four new vaccine-capable sites
hundred patients per site at most. Drug trials are short in online by end of 2008 will add to this capacity, in particular
duration (follow-up may be as little as 28 days) and sites being groomed for large-scale phase III enrolments
enrolment is simpler to manage than vaccine trial enrolment. (Blantyre Malaria Project Research Clinic, Ndirande, Blantyre
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and CDC/KEMRI). We note, though, that both are young sites collective restrictions mean that only 3 or 4 sites can enrol a
with no previous vaccine trial experience and limited drug guaranteed 1,000-1,200 infants per year; with the remaining
trial experience, which may lead to some “operational sites enrolling perhaps 600-1,000 infants per year each,
capping” of their enrolment capacity. The other new vaccine although this would be expected to increase rapidly as
sites (TDRC-Ndola and Noguchi) will not immediately con- younger sites, in particular, increase their ability to access
tribute to capacity as they are first being readied for small infants and manage trials.
trials. Even when all proposed new sites are online, there will
The collective capacity across all current sites is estimated at
still be a gap in Central African vaccine enrolment sites,
around 8,400 to 12,800 infants per year, allowing for a cap
including an absence of sites in Nigeria.
of 1,200 patients per site. (The site cap reflects the fact that
All current “all purpose” licensure sites can conduct vaccine phase III malaria trials need a broad epidemiological and geo-
trials in adults, therefore the minimal adult vaccine enrolment graphic spread; patients cannot be enrolled en masse at two
demand to 2012 is likely to be easily met. or three sites as they might be for a pneumonia vaccine trial.)
The lower enrolment figure of around 8,400 is very conserva-
Eleven of these twelve “all purpose” sites also have experi-
tive: it assumes constrained patient access at half the mature
ence in conducting phase IIb trials in children (the CNRFP site
sites and slow build-up to operational capacity at all young
in Burkina Faso is the exception). However, although most of
sites. The higher figure is likewise optimistic: it assumes that
these sites can conduct a large phase IIb trial in children, not
all sites, young or mature, even sites with no infant licensure
all could do so simultaneous-
experience, will be able to enrol and manage 1,000 infants
ly with a large phase III
per year by mid-2008.
vaccine trial, such as the
We have RTS,S trials that many are Based on this analysis, infant enrolment margins are uncom-
enough now committed to running. fortably narrow if low-end estimates eventuate. This is even
malaria The mature sites are better more so since a product developer may be unable to secure
placed in this regard, having all vaccine sites at a given time: every unavailable high-
licensure
greater management and enrolment site drops the infant enrolment quota by 1,000
sites in Africa, operational experience and patients or more per year, bringing total enrolment supply
if well also greater ability to dangerously close to falling short of enrolment demand.
managed “segment” populations to Given this, the decision to add two additional large-enrolling
allow child enrolments in one sites by 2008 is timely, as this will provide a safety buffer of
area and infants in another; an additional 1,500-2,000 infants per year; as well as the
but these sites may be more modest additional enrolment capacity at TDRC-Ndola
occupied on large-scale non-malarial trials which constitute an and Noguchi. In our assessment, these upgrades will close
increasing part of their work. Younger “all purpose sites”, on the short-term capacity gap for infant vaccine enrolments if
the other hand, may have difficulty simultaneously conducting trial allocation is well managed. Close attention will also be
two large vaccine trials (particularly if also doing drug or phase needed to avoid spare capacity once the RTS,S trials are
IV trials), while the very new sites being brought online now completed at end 2010.
would be unlikely to be able to do so. Given this, child
At an individual project level, the decision by RTS,S’ developers
enrolment demand in 2009/10 may put strain on the existing
to expand from the proposed eight phase III sites to a
site network, and will require careful management to avoid
network of around 10 sites also seems prudent. With an
either overloading young sites, or failing to secure mature sites.
enrolment target of 7,500 infants/year for RTS,S, the relative-
Infant enrolments present similar issues, since not all of the ly small number of original sites was at risk of shortfalls if
vaccine licensure sites have the large infant patient loads, younger sites failed to increase their operational capacity
good access to these patients, and high management sufficiently quickly. It was not improbable that enrolments
capacity that are pre-requisites for large-scale infant vaccine might have struggled to reach 7,500, particularly in the first
trials such as the upcoming phase III RTS,S study. In particu- year of the RTS,S phase III trial. The decision to expand the
lar, the infant enrolment capacity of the young and upcoming site network not only widens the safety margin for the
sites is as yet untested, as most have not conducted a vaccine product developer but, importantly, also takes pressure off
licensure trial in this age group; several also have limited young and first-time vaccine sites to deliver large infant
enrolment capacity, at least in the short-to-mid term. These enrolments very early in their development curve.
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Table 12. Projected enrolments per year for phase IV trials to 2012
TRIAL DESCRIPTION PROJECTED ENROLMENTS

Year 1 Year 2 Year 3 Year 4 Year 5
IEC* stage I 5,550 12,950 9,250 7,400 7,400
Observational (Pharmacovigilance) 6,000 14,000 16,000 22,000 24,000
Safety & Effectiveness 3,000 7,000 8,000 11,000 9,000
TOTALS PER YEAR 18,750 43,750 44,450 55,800 53,000
* Information, Education and Communication
2.3.3 PHASE IV TRIAL SITES vaccine developers looking

for sites for large phase IIb
2.3.3 (I) DEMAND FOR PHASE IV TRIAL SITES trials in children may begin
As discussed above, there is not yet agreement on how phase to feel the pinch if available Phase IV
IV trials should be constructed or who should conduct these, licensure sites are tied up trials may
although discussions to set up a phase IV trials consortium doing phase IV trials: this is compete with
(possibly linked to the INDEPTH group) are well underway. especially the case for young
and new licensure sites that
licensure trials
This consortium would trial new malaria drugs coming to
have plenty of patients, but
for sites and
registration and would be involved in working with govern-
ments to develop phase IV protocols for general use. are less likely to have the enrolments
capability to simultaneously
Given the uncertain situation with respect to phase IV trials, manage multiple large trials,
we therefore restrict ourselves to discussion of one scenario - for instance a phase IIb trial
the planned Lapdap phase IV programme (see page 28) - in one age group, a phase IV
while emphasising that this is only one possibility of many, population trial and, in some
and is provided as food for thought rather than anything cases, a phase III RTS,S infant
more concrete. As this scenario did not specify timeframes, trial.
we also drew on the Lang model for phase IV trial durations11.
A second key point is that the above figures may seem large
If enrolments for phase IV trials of new malaria products are but they are, if anything, an underestimate. They do not take
based on the planned Lapdap programme, an estimated into account enrolment associated with other current and
nearly 215,000 patients would need to be enrolled at phase potential community based programmes, including:
IV trial sites over the next five years, with a peak annual
demand of 50,000-55,000 patients (see Table 12). More than The MIP Consortium study (Malaria in Pregnancy) to assess
half these enrolments would be in subjects under 5-years of the use of anti-malarials drugs in pregnant women (size
age, with a significant proportion being 6-weeks to unknown)
18-months old (the infant group that is of central importance The ACT Consortium, which plans to undertake more
to malaria vaccine trials). “community based” comparative studies of new ACTs
(size unknown)
These figures raise two important issues. Firstly, these Formal ACT comparator studies funded by the EDCTP are
enrolments will need to be very carefully managed and/or also currently underway, but will be finished by mid-2008,
coordinated with vaccine licensure trials to avoid competition before phase IV enrolment demand peaks.
for sites and patients. The risk of “infant competition” has
been decreased by the decision of RTS,S’ product developers
to reserve more sites for phase III RTS,S trials. However,
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WHO/TDR is also considering a series of studies including: Uganda Ministry of Health Vector Control Division,
Kampala, Uganda
A multi-centre study focussed on increasing access to
College of Medicine, University of Ibadan, Nigeria
ACTs within the Home Management for Malaria strategy,
which envisions enrolling 0.5 million infants and children In addition, most of the 23 licensure-standard sites listed
under 5-years of age in 6 countries. (While not enrolled previously are currently capable of conducting phase IV trials,
through formal trials, these children would nevertheless the exceptions being small sites such as Noguchi, or sites
be unavailable for such enrolment.) without a DSS such as the Komfo Anokye Teaching Hospital
Integrated malaria treatment multi-centre trials, enrolling (KATH) in Kumasi, Ghana. Using licensure sites for phase IV
an estimated 0.5 million subjects or more at a probable trials is, however, less than ideal from an efficiency perspective
10 sites (still at design stage; sites unknown) (see discussion on page 65). No estimate of phase IV capacity
An integrated management of malaria and pneumonia gaps can be made until a phase IV approach is decided.
multi-centre study (size and sites unknown).
These groups are each seeking funding to conduct trials in
different patient groups at different trial sites and for
somewhat different purposes. Given the very large enrolment
numbers and very substantial cost of conducting these trials
(even without the WHO/TDR studies), it would seem wise to
seek efficiencies in the process.
Given this, we welcome the interest of The Bill & Melinda
Gates Foundation, as a potential sponsor of several of these
groups, in co-ordinating a more organised response to these
demands, as well as to formal label extension trials planned
by MMV. Two-way and head-to-head product trials would
also greatly reduce these enrolment figures e.g. trialling new
ACTs against each other rather than trialling each product
alone against existing treatments. The head-to-head
approach would also provide information to national policy-
makers in Africa - and to ACT subsidy funders - far more
quickly, allowing them to make rational choices based on
efficacy and price.
2.3.3 (II) SUPPLY OF PHASE IV SITES
As noted, many more sites in Africa are capable of conducting

phase IV studies than formal licensure trials. Experts at
WHO/TDR and elsewhere identified 8 sites as “very good”
potential phase IV sites, with a further 30-plus sites
mentioned or proposed by them as phase IV centres. None of
these sites are licensure-standard sites, although the Ibadan
site is slated for upgrade to a drug licensure site as part of the
MCTA initiative (see page 44). The eight nominated “very
good” sites (although doubtless more exist) are:
Centre Muraz, Burkina Faso
University of Yaounde 1, Cameroun
CTCPT, University of Ghana Medical School, Ghana
Muhimbili University, Tanzania
Makerere University Medical School, Kampala,
Uganda Med-Biotech Laboratories, Kampala,
51
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> 03 MANAGING THE TRIAL
SECTION
SITE NETWORK
3.1 WHERE WE ARE TODAY

Trial site development is an area where funders and sites can justly afford to
congratulate themselves. Up to the late 1990s there were relatively few sites suitable for
licensure-standard malaria product trials - nor were they greatly needed, given the limited
number of malaria products in the clinical pipeline at that time. A handful of mature sites,
often European-linked, were able to conduct most of the necessary work, e.g. the
Wellcome Trust sites in Kenya, the UK MRC sites in The Gambia and the Hospital
Albert Schweitzer site in Gabon.
However, as malaria product R&D began to increase in the However, although we believe the current licensure site
late 1990s and early 2000s, funders and sites moved to put network is sufficient in terms of numbers, there is still work
the necessary infrastructure in place (albeit sometimes in a to be done. The focus on the six mature sites as the linchpin
“just in time” fashion). Since 2001, seven new licensure of malaria trials will decrease as their malaria rates drop
sites have come on line, the majority of these funded by US and/or as they continue their expansion into other disease
groups including the NIH, US Army and MCTA/MVI initiative areas. Increasingly, the future of malaria trials will lie with the
funded by the Bill & Melinda Gates Foundation.XXXVII The new young sites, whose high malarial populations and birth
exception is CISM-Manhiça, funded by the Spanish rates and (at least for the moment) primary focus on malaria
Government, while NIMR Tanga has received funding from make them ideally suited to malaria product trials.
the EDCTP as well as from the MCTA. Four of these sites are
This presents two new challenges to policy-makers and
already considered fully mature, and all are now drug and
funders. The first will be to sustain these young and new
vaccine capable.
licensure sites and provide the right kind of support to bring
Additional funding is now being invested to bring a further them to their mature potential. The second challenge will be
six licensure sites online by end 2008, of which four will be to manage the flow of product trials to all sites over the next
brought to vaccine licensure standard and two to drug five years in a way that is synergistic with, rather than coun-
standard.XXXVIII Again, the bulk of this funding is MCTA/MVI terproductive to site growth.
funding linked to RTS,S vaccine trial site upgrades; the
exception is TDRC-Ndola, whose upgrade is funded through
AMANET. 3.2 CHALLENGE ONE: MATURING
As a result of these investments, the malaria licensure site AND SUSTAINING YOUNG
network has grown from 5-6 sites in the 1990s, to 18 sites in AND NEW LICENSURE SITES
2007 and will reach 23 sites in 2008. (One current site,
The growth curve to maturity
MIAM-Choma is likely to be lost to this network in the future
due to rapidly dropping malaria rates.) Successful licensure sites tend to have a similar upgrade
trajectory:
As noted previously, we believe this network of 23 sites will
be sufficient for malaria product trials out to 2012. This new
network is not only bigger than before, but its structure is a High-quality research studies
better match for projected product trials than anything we
Large-scale intervention trials such as IPTi
have seen to date. More sites are capable of more types of
trials than previously (there will be 16 all purpose drug and Drug licensure trials
vaccine sites compared to the existing 12); and current phase Small-scale vaccine trials
III site expansions are making new patient groups available at
existing sites, which will increasingly allow sites to segment Large vaccine trials
patients into different disease, age and product trials.
XXXVII These seven sites are (date of first licensure trial is in brackets): CISM Manhiça, Mozambique (2001); USAMRU-K, Kenya (2002); MRTC Bandiagara, Mali (2003);
Bagamoyo, linked to the Ifakara Health Research and Development Centre, Tanzania (2005); Agogo, linked to KCCR-SMS Kumasi, Ghana (2005); Korogwe, linked to
NIMR Tanga, Tanzania (2006); and Kintampo, linked to KHRC, Kintampo, Ghana (2006)
XXXVIII These six sites are: Blantyre Malaria Project Research Clinic- Ndirande, Blantyre and CDC-KEMRI, being upgraded to large vaccine capacity; TDRC-Ndola and Noguchi,
being upgraded to small vaccine capacity; and MRL-Ibadan and Cheikh Anta Diop-Senegal, to drug licensure standard
52 MANAGING THE TRIAL SITE NETWORK > THE MALARIA PRODUCT PIPELINE
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For example, this pattern was followed at KHRC in Kintampo, Time and cost to negotiate the growth curve
Ghana, Bagamoyo, USAMRU-K and HAS, Gabon. Several trial
We examined the time and cost of bringing sites to licensure
site managers and advisors highlighted this “organic” growth
standard, focussing on the seven sites rolled out since 2000
process as crucial, noting that gradual expansion to new
(site upgrades prior to 2000 were considered less topical).
satellite areas and communities was highly preferable to rapid
One would expect these development costs and times to be
expansion to accommodate more demanding licensure trials.
highly variable depending on the original state of the site, its
Sites that have experience in conducting large scale non-
geographical location, scien-
licensure malaria trials and early experience in drug licensure
tific connections, and so
trials are also likely to transition more quickly and efficiently
forth. However, a review of
to licensure-standard vaccine trial capability, since they will
A site can be new sites and their upgrade
have already developed the technical licensure skills and some
costs and development trajec-
of the large-scale management skills that are pre-requisites for upgraded in
tories produced surprisingly
managing longer, more complex vaccine product trials. two years consistent - and surprisingly
Once sites approach maturity, they also tend to expand into
for around low - ballpark figures.
other disease areas. This is the case even though most sites US$2 million
The time to build a trial site
were initially set up for malaria studies (e.g. staffed with
from scratch was around five
malaria experts, baseline malaria epidemiology conducted,
years, broken down into two
etc.). For example, several mature sites have moved into trials
distinct tranches:
in other diseases because “there wasn’t enough malaria (or
malaria work) to keep the site busy”: 3 years from site foundation to the point at which it could
conduct fairly sophisticated non-licensure research
USAMRU-K expanded into rotavirus, diarrhoea, pneumo-
2 years for the more common (and possibly more efficient)
coccus and HIV in 2005
model of upgrading an existing good research site to
KEMRI Kilifi conducts rotavirus, pneumococcal, meningo-
licensure standard.
coccal and AIDS trials
The MRC Gambia network conducts pneumococcal, Total cost from first site foundation to licensure status was
meningitis, diarrhoea and TB trials. Outside malaria around US$3-3.5 million for the few sites where full figures
season, staff are cross-deployed to other programmes were available. (We emphasise, however, that this figure is
(e.g. TB) or to different tasks (e.g. epidemiological analysis included mainly for completeness sake as it is unlikely and
or laboratory work) probably undesirable that new sites would be built from the
Manhiça has moved into Respiratory Tract Infections (RTIs), ground up at this point.) A more common scenario was a
HIV, diarrhoea and pneumonia trials, which now represent second tranche upgrade i.e. an existing site being upgraded
50% of their work and still growing. from research trial capacity (intervention or observation
studies) to licensure trial capacity. These partial or second
The only mature sites that still focus solely on malaria are the
tranche upgrades were completed at an average cost of
two most recently established, and both are already seeking
under US$2 million per site. One site funded its own
to diversify. The MRTC in Mali (2003) is looking at possible
licensure-standard upgrade for two years prior to receiving
bacterial vaccine work, as conducted at the nearby but
external investment: in this case, the process was cheaper at
unrelated Bamako City site. Bagamoyo/Ifakara (2005) is also
around US$820,000 but took around twice as long, at four
interested in expanding, although it is currently restricted
years in all. This suggests that an existing research site can
from doing so by lack of investment funding.
potentially be upgraded to licensure standard in 2 years for
As expected, the young licensure sites are still largely around US$2 million.
focussed on malaria, noting that “we are just getting estab-
Typical site development vignettes are below:
lished as a malaria licensure trials centre” and that “a broader
scope is not going to happen any time soon as the site is just The CISM Manhiça trial site was built from the ground up
establishing”. However, even among these very young sites, in five years, between 1996 and 2001, when it conducted
half are already thinking and talking about expanding to HIV, its first licensure trial. Building site infrastructure took
respiratory and diarrhoeal diseases in the future, “if the site around 3 years, including establishing relationships with
grows”. the local hospital and community, developing baseline DSS
MANAGING THE TRIAL SITE NETWORK > THE MALARIA PRODUCT PIPELINE 53
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data and a hospital surveillance system linked to this data, previous upgrade investments and also reflects the generally
creating laboratory and clinical infrastructure, and lower costs of drug-site upgrades. In practice, the MCTA plan
employing and training staff. By 1999/2000, the site was is now changing somewhat as more sites than originally
able to conduct quite complex research and became inter- planned are being converted to vaccine rather than drug use:
ested in licensure trials. The second tranche upgrade to this may affect total cost.
licensure-standard took 2 years, including putting in place
What are the features of a mature site?
GCP, GLP, SOP, and quality control and quality assurance
training. Manhiça commenced enrolment of over 2,000 In an effort to determine what makes a site successful and
children in the phase IIb RTS,S vaccine trial in 2001. This sustainable, we analysed the characteristics of mature licensure
two tranche upgrade over a five-year period was largely standard sites. All six mature licensure sites shared the
financed out of modest core funding provided by the following:
Spanish Agency for International Cooperation
The MRTC-Mali built the Bandiagara site to licensure
A long-standing relationship of more than 10
standard over five-years, between 1998 and 2003. First
years, and in some cases 50-60 years, with a
tranche development of site infrastructure took 3 years,
Western institution
with a decision made in 2001 to commence a licensure-
Long-term core funding from a Western
standard upgrade. Licensure-standard upgrade took two
government or institution covering a minimum
years, and included GCP, GLP, and SOP training, bioinfor-
20% of core costs, and in some cases up to 50%*
matics and epidemiology training, building two specific
A core staff of Principal Investigators with
vaccines testing centres, and a satellite ground station
substantial licensure trial experience
installation. An NIH grant of US$3.3 million received over
On-site staff training programmes XXXIX
an 8-year period between 1998 and 2006 financed both
Diversification into other disease areas once
development tranches i.e. site build-up and licensure-
the site is established, including AIDS, TB,
standard upgrade, and continued well after the first
rotavirus, pneumonia, meningitis, diarrhoeal
licensure trial
illnesses and RTIs.
The USAMRU-K site at Kombewa and nearby Kisumu, Kenya
was built from scratch specifically to conduct malaria vaccine * The USAMRU-K site funds itself entirely from projects, but receives
substantial “captive” business from US Army malaria trials
trials, with construction beginning in 2002. Three main facil-
ities were developed over a 3-year period including the
Kombewa clinical research centre, the Kondelli research lab-
oratory, and the specialist paediatric tertiary care facility It is notable that all these “success” characteristics relate to
co-located with the New Nyanza Provincial General Hospital. operational or managerial aspects. There was no correlation
Total cost was around US$2 million. Their first vaccine trial, between successful sites and their size, project income, or
a Phase Ib trial of WRAIR/GSK blood stage vaccine MSP-1, level of core costs; or with the presence or absence of a DSS
was conducted in 2003. system. For instance, individual site yearly income varied from
US$3.5 million to US$30 million, and yearly core funding for
Comparative site upgrade costs are also available from
the trial centres from as little as US$0.5 million to nearly
“umbrella” sources such as product development groups and
US$15 million.
the MCTA. Collectively, the MCTA, MVI, and MMV have
funded, or are funding, upgrades at 14 sites designated for Somewhat surprisingly, despite their highly diversified disease
clinical trials of MVI and/or MMV products. From 2006-2010, and income base, none of the mature sites were self-sustain-
the total investment allocated to bring these 14 sites to ing based on project income; indeed all sites were very clear
licensure-standard was US$15.8 million. This sum was used that was an impossibility (USAMRU-K is excluded from this
to fund: RTS,S-linked upgrades of four mature vaccine sites discussion due to its special funding situation, as noted above).
to run phase III infant trials; upgrading four further sites to In explanation, site directors noted that their overheads were
conduct their first vaccine trials (generally against a back- normally 20-30% but that most project funders would pay
ground of drug licensure experience); and the less expensive nothing near this level. As one site noted, “Donors keep
task of upgrading eight research sites to do drug licensure trying to restrict overheads, but still expect sites to be sustain-
trials. This figure is lower than the US$2 million average able”. While DANIDA and the European Commission
noted above, as MCTA investment is often additional to routinely pay 20% overheads, many product development
XXXIX The exception is the Bagamoyo/Ifakara Health Research & Development Centre (IHRDC), Tanzania
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groups seek to keep overheads at 15% or even as low as year over long periods (1995-1998 and 2003-2007, both
10%. Even experienced sites cannot survive without core for measles vaccine studies). The site has access to maternity
funding under these conditions: “If sustainability is defined as and paediatric inpatient wards, three satellite health centres,
self-funding through project work, then we would not be and links to a number of Danish academic institutions
classified as sustainable…”; “You would die if you tried to The CRSN drug licensure site in Nouna (Burkina Faso) also
survive on overheads”. has a good likelihood of successful transition to vaccine
trials in the near future. They initially conducted large
All sites agreed that the single most vital component of
intervention trials, such as ITN efficacy, and moved to
success was core funding, even if modest, so long as it was
malaria drug licensure studies in 2003. They have strong
sustained over time: “The support of our core funder is vital
links with the University of Heidelberg (Germany) and
to our survival”; “a committed funder that provides core
access to a DSS with a population of 76,000
funding is fundamental”. Core funding allowed sites to
CNRFP-Burkina Faso is a promising site for larger-scale
support basic platforms and structures (such as DSS) and
trials but is limited by lack
retain experienced core staff in the lulls between projects.
of local infrastructure,
Core funding was also seen as important for site independ-
including public water
ence, allowing sites to reject product trials that were “not a
and electricity (the site Low core
serious endeavour”; and was viewed as essential for the
currently uses on-site funding and
conduct of high-quality research unrelated to product trials. inadequate
generators and wells). Its
Nevertheless, despite noting its importance, no sites inter-
viewed wanted to be entirely reliant on core funding, with
potentially high infant overheads
most arguing that a mix of core and project funding was both
enrolment capacity, and make it
optimal and “healthy”.
extensive experience in impossible
drug licensure trials (and for young
Are funders taking these lessons on board? one small vaccine licensure
sites to be self-
trial) would nevertheless
Growth trajectories
make it an excellent site
sustaining
As we have seen, successful site growth is often organic, for larger vaccine trials if
moving from high-level research studies into small and later these infrastructure issues
large malaria licensure trials, followed by diversification into could be resolved.
other disease areas to ensure a broad income base. This tra-
In practice, however, site selection for investment and devel-
jectory allows sites to build relationships with their local
opment has not always followed this pattern. Some funders
communities and health systems and to develop at a pace
deliberately choose a site with limited experience as part of
they feel they can manage. It is also efficient from the
their capacity-building remit (e.g. WHO/TDRs choice of drug
product developer and funder perspective, since a smaller
licensure sites was partly guided by this principle); while
investment of time, resources and energy is required to move
several sites have also been upgraded without the promise of
a site to the next milestone along the development trajecto-
upcoming product trials. The pressure to find additional sites
ry than to accelerate it through several development levels in
for RTS,S phase III trials also means that some sites are now
a short time.
being rapidly accelerated from non-licensure or early
Upgrades of this kind have been seen with the transition of licensure status to phase III vaccine readiness, without the
phase IIb RTS,S sites to phase III sites; and with the planned benefit of a phase Ib or IIb stepping stone, for example BMP-
upgrades of partially-experienced drug sites like Ibadan and Blantyre and CDC-KEMRI. While perhaps not the easiest
Cheikh Anta Diop to fully-fledged drug licensure sites. approach, this can work if the site has a promising profile and
Applying these lessons can also help funders and product plenty of support. For example, CDC-KEMRI has never
developers to identify high-malaria population sites that may conducted a licensure trial, but has extensive experience in
be suitable for upgrade. For instance: large interventional field trials (e.g. IPTi); access to a large
population in the Nyanza Province (around 130,000 people);
Bandim in Guinea Bissau has no licensure trial experience,
a well developed malaria laboratory, ability to perform stan-
but could be expected to reach vaccine licensure standard
dardised and sophisticated research assays; links to the CDC;
fairly quickly. It has extensive experience in infant trials,
and a core team that has been praised by experts as “very
including non-licensure infant vaccine studies, with
strong”. They will also benefit greatly from being partnered
demonstrated enrolment of 1,800 to 2,000 infants per
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with the mature USAMRU-K vaccine site when they conduct product-specific (e.g. construction of labs to support a
their first licensure trials. vaccine trial)
Project overheads were diverted to pay for core require-
“Success” feature gaps
ments (e.g. DSS support or salaries of core staff not
Distilling findings from various sections of this report suggests occupied on the project) while infrastructure was allowed
that young licensure sites are likely to increasingly be the to run down
future of malaria vaccine trials. Nevertheless, review of these Core staff were kept to a minimum, with large numbers of
sites showed that virtually none currently receive the kinds project staff being contracted and dismissed as projects
of support identified above as central to the creation of a came and went. Some sites reported staff fluctuations as
successful mature site: large as 150 staff (dropping from 400 to 250 staff)
between one year and the next.
Only 2 of the 6 sites were affiliated with a Western institu-
tion (one with a German Institute and one with a German The lack of core funding to sustain these young vaccine sites
university) appeared to relate to policy and funding preferences rather
No sites received core funding from a Western institution; than financial constraints. As one experienced trial site
3 received modest but continuous funding from their local Director observed, the problem was that, “everybody wants
government; while 2 others received only occasional con- to fund the sexy stuff but nobody wants to fund the guy who
tributions. This has restricted growth and diversification at cuts the grass on your compound”.
most sites
4 of the 6 sites relied on project funding for 95% or more
of their income; while all sites reported being able to charge
overheads of only 10-15% (the Hospital Albert Schweitzer
in Gabon and the CNRFP in Burkina Faso occasionally
charged up to 20%)
Most sites did not have a formal on-site staff training
programme
Most had only a small core staff of Principal Investigators
with licensure trial experience
These sites had large malaria loads and high birth rates,
but were held back by lack of the financial and manage-
ment skills needed to handle multiple simultaneous trials, “Everybody
funders and income streams. wants to fund
The combination of low or no core funding and chronically the sexy stuff
inadequate project overheads made it difficult or impossible but nobody
for these sites to invest in growth or to sustain themselves wants to fund
between projects. Furthermore, because income was largely the guy who
project dependent, sites also needed to manage large income cuts the grass
fluctuations from year-to-year. This was, “a vicious cycle, on your
where we need more projects to get funding to build up, but compound”
we need to be built up before we can get more projects”.
As with mature sites, all young sites felt that core funding
was the number one priority; and some specifically described
core funding as, “preferable to one-off upgrades or upgrades
linked to projects”. However, in the absence of either core
funding or adequate overheads, these young sites survived by
employing a range of adaptive behaviours:
Capacity building or growth was conducted only when
specific grants could be obtained or, more commonly, was
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3.3 CHALLENGE TWO: sites at the start of their development trajectory are more
MAXIMISING SYNERGIES suitable for phase IV trials e.g. drug sites or sites now being
brought to licensure standard. Indeed, some may be particu-
BETWEEN SITES AND TRIALS
larly well suited to phase IV trials courtesy of their large
Placing trials efficiently populations, high malaria rates, and previous drug trial
experience (e.g. Oubritenga, Nouna and Ndola); and all
Allocating trials to the “right” site is a simple and effective
would benefit from the additional income and experience
way to sustain and mature the current licensure site network.
associated with conducting phase IV trials.
A well placed trial can help move a site along the development
trajectory. In other words, the development trajectory provides Nevertheless, phase IV-type
a helpful template for thinking about capacity building, trials have often been cond-
allowing us to match sites at different points of the trajecto- ucted at licensure-standard
ry with product development trials that help to advance them sites (e.g. Ifakara, Navrongo
to the next stage. For example, large phase IV trials, including and CISM Manhiça) and an
A well placed
IPTi and IPTp trials, may be a useful step for sites planning to examination of current phase
trial can move
move into later licensure work; small label-extension trials IV proposals shows that a site along its
may be helpful for sites building their drug licensure experi- many licensure sites are still development
ence; and the plethora of small vaccine trials due in the next being considered for phase IV trajectory
5 years (perhaps as many as 40) may be helpful as a first enrolments (see Table 13).
introduction to vaccine trials for drug licensure sites or sites Some of these sites will have
now being upgraded to licensure standard. been chosen for good policy
reasons e.g., as the best site
While not all trials can be used as development levers, at a
to help define regional treatment policy, but others may
minimum they should ideally be allocated to provide as close
represent a more reflexive reaching for the “best” site rather
a match as possible between the technical demands of the
than the most appropriate site.
trial and the technical skills of the chosen site: having a
high-tech site conduct a low-tech trial does not represent the Managing lulls and peaks
best resource use. Allocation of phase IV trials offers a good
As we saw, trial site demand over the five years to 2012
example. Mature licensure sites will often be offered phase
presents a fluctuating picture, however a few key points are
IV-type trials and it may be strongly in the interests of both
worth noting:
the site and of policy-makers to do them, since both want a
quick and reliable decision on the suitability of new malaria We anticipate a steady stream of small drug and vaccine
treatments for the local population and health system. trials (under 100 patients), which are ideal for new and
However, placing phase IV trials at experienced licensure sites proposed licensure sites to cut their teeth on
also has a downside. It represents lost capacity-building 2009-2010 are likely be high demand years for trial sites
opportunities for alternative non-licensure sites seeking to due to overlapping phase IIb and phase III vaccine trials,
gain experience and funding to grow; it increases costs, since which will impose strains on the management capacity of
licensure sites are more expensive to run; and it puts phase IV young sites, and the availability of mature sites (patient
enrolments in direct competition with licensure trials except numbers are not an issue)
at the very largest sites (Phase IV trials in the 6-month to There is potential competition between phase IV child and
5-year age group have a substantial overlap with the under infant enrolments and phase IIb vaccine licensure trials
18-month age group needed for phase III vaccine trials; while (again, due to management capacity rather than patient
younger sites may not be able to manage two or more numbers)
large-scale trials simultaneously.). After 2010, there will be significant “spare” capacity
(including for infant enrolments), which could be available
In general, it is highly inefficient for donors to upgrade inex-
for non-malaria licensure trials if the young and new
perienced sites to do licensure trials while more experienced
licensure sites were in a position to diversify by that time.
(and expensive) licensure sites carry out less demanding
phase IV trials. This is particularly the case for vaccine Currently, issues such as these are difficult to resolve, with
licensure sites, which are in short supply and will be sorely trial site allocation suffering from a form of “public good”
needed for RTS,S phase III development.XL Where possible, syndrome. While all malaria groups would undoubtedly agree
XL This issue has largely been pre-empted by the recent decision of RTS,S developers to sign-up ten licensure sites for the RTS,S programme instead of eight. We note,
though, that this reflected a unilateral developer decision rather than an efficient, well planned overarching approach to use of trial sites
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Table 13. List of proposed phase IV trial site usage
ACT Phase IV TDR “Home Mgmt Shortlisted EDCTP ACT Slated for
Consortium Consortium* of Malaria” trials LAPDAP phase 4-arm phase III RTS,S
IV sites comparator trials vaccine trials
MATURE LICENSURE SITES
USAMRU-K, Kisumu, Kenya X

Wellcome Trust/ KEMRI, Kilifi, Kenya ? X X
MRTC sites, Mali X
CISM Manhica, Mozambique ? X X
Bagamoyo/Ifakara Health Research & Development Centre, Tanzania X X
MRC sites, Gambia X ?
YOUNG LICENSURE SITES
Hospital Albert Schweitzer, Gabon X X X X

Agogo Clinical Trial Centre, KCCR, Ghana X
KHRC, Kintampo, Ghana X ? X
NIMR Tanga, Tanzania X ? X X X
Navrongo Health Research Centre, Ghana ?
CNRFP, Oubritenga/Ouagoudougou, Burkina Faso X ?
LICENSURE-STANDARD DRUG SITES
CRSN, Nouna, Burkina Faso ? X X

Blantyre Malaria Project (BMP) Research Clinic, Ndirande, Blantyre, Malawi X
QE Hospital, (MLW), Blantyre, Malawi X
MIAM, Choma, Zambia
TDRC, Ndola, Zambia X X
KATH, Kumasi, Ghana X
NEARLY-READY (TO LICENSURE-STANDARD) SITES
CDC/KEMRI, Kisumu, Kenya ? X

MRL, University of Ibadan, Nigeria X X X
Noguchi Memorial Institute, Ghana X
University Cheikh Anta Diop, Senegal X
Niakhar Institut de recherche pour le developpement, Senegal X ? ?
PHASE IV SITES
Médecins Sans Frontières Epicentre, Mbarara, Uganda X

Bandim Health Project, Guinea Bissau ?
Centre Muraz, Burkina Faso X X
University of Yaounde 1, Cameroun X X
Centre for Tropical Clinical Pharmacology and Therapeutics (CTCPT),
University of Ghana Medical School, Ghana X
Drug Research Unit, College of Medicine, University of Ibadan, Nigeria X X
Muhimbili University, Tanzania X
Makerere University Medical School, Uganda X ? X X
Med-Biotech Laboratories, Uganda X
Department of Paediatrics, University of Calabar, Cross River State, Nigeria ? X
Ministry of Health Vector Control Division, Uganda X X
* These sites have been mentioned, but not finalised

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that the site network should be used rationally with trials

placed at the most suitable sites, in practice, when it comes
to their own trials, individual groups often prefer to go to the
tried-and-true mature sites, even when these are technically
over-skilled for the trial in question. Individual sites also have
every incentive to sign up new trials, even trials well below
their capacity, although these might have greater positive
spin-offs if placed elsewhere. At the moment, there is simply
no incentive to allocate trials more rationally - indeed, there
is every incentive not to do so.
Even if such incentives did exist, some co-ordinating principle
(as opposed to organisation) would be needed to help
developers co-ordinate their plans. The next stage of our
research will work with trial sites and site funders to generate
a range of incentives and proposals that could help improve
and co-ordinate trial flows for both developers and the sites
themselves.
59
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VACCINE POLICY
SECTION
> 04 PRICE-TAGS
Different scientific and policy approaches in the malaria product development field have
dramatically different, and sometimes unplanned, resource implications. In previous
sections, we saw the impact of different policy choices on drug trial costs and product
numbers. This section explores the impact of potential policy choices in the vaccine field.
A wide range of factors impact on the cost, duration and This approach, which provides a single value rather than a
success of malaria vaccine development. These include scien- value range for each output, and which changes inputs in
tific and technical aspects that policy-makers and funders isolation, was chosen purely to facilitate the exercise of
must address (e.g. higher or lower scientific attrition rates; isolating and measuring policy impact. It is meant to highlight
acceptance of a more or less efficacious vaccine; and relative changes, not absolute values. These figures are
presence or absence of a challenge model that would allow indicative not predictive. In the same vein, while the baseline
ineffective blood-stage vaccines to be identifed prior to field scenario represents a plausible future outcome, we also
trials). They also include pure policy choices (e.g. regulatory selected both reasonable and more extreme scenarios around
decisions affecting trial complexity; choice of desired trial the baseline in order to better illustrate the downstream
endpoint to support public health use; and level of invest- impact of policy decisions. These scenarios are not meant to
ment in early research to feed the malaria vaccine pipeline). suggest that these policies would be put in place, and many
demonstrably would not.
In an effort to provide policy-makers with information on the
potential impact of these choices, we have modelled the
flow-on costs of a range of policy and scientific settings,
including their clinical development cost, “time” cost, and 4.1 SCENARIOS
associated enrolment burden over the five-year period to
The scenarios below are ranked by impact on total invest-
2012. Clinical development cost refers to the direct cost of
ment and total enrolments, which generally go
clinical trials, including field costs and centralised costs as
hand-in-hand. The exception is the two scenarios at the end
described above. “Time” cost refers to how quickly the
of the list, which primarily impact on portfolio progression.
global portfolio is developed, i.e. how many projects have
The baseline scenario, although clearly in the middle in terms
advanced how far towards registration by 2012. Enrolment
of cost and enrolment impact, is put at the head of this list
burden refers to the number of adult, child and infant enrol-
for ease of comparison.
ments each approach will require, as a proxy for trial site
demand. RTS,S is not included in this modelling, since its Scenario 1: The baseline
development programme is already finalised i.e. it would
The baseline scenario has the following resource and devel-
have simply appeared as a fixed figure in every scenario.
opment implications:
Finally, we measure the impact of one further variable -
changing rates of malaria incidence in some areas of Africa.
Although beyond the scope of this report, this will neverthe- Clinical development cost of the global vaccine
less need to be taken into account in forward planning and portfolio is US$110 million out to 2012. By that time,
is, indeed, one of the more likely scenarios. 13 candidates will have reached phase IIb trials in
children; and around 1,000 adults and 11,500
As noted above, each scientific and policy setting has a quite
children will have been enrolled in malaria vaccine
different impact on the three key areas. To make these
trials across Africa. One vaccine candidate has already
impacts clearer, we first developed a “baseline scenario” and
moved to the next step, phase Ib safety trials in
then changed input variables one at a time to measure their
infants, with 60 infants enrolled in this trial by 2012.
effect. The baseline scenario is based on the current global
vaccine portfolio, which is modelled forward to 2012 using
the standard Clinical Development Plan, mid-range attrition
rates, mid-range costs per phase and standard trial sizes for
each phase based, where relevant, on current malaria
incidence.XLI
XLI For standard Clinical Development Plan, see Annexe 3b. Trial size for phase Ib field safety trials was fixed at the average trial size. Phase IIb trial size varies widely
depending on what the trial is designed to show, therefore we chose baseline parameters that reflected a common historical ‘profile’ for trial design (i.e., a binary calcula-
tion based on a vaccine with 50% efficacy against a primary endpoint of first clinical episode of malaria in a control population), with an average of 17% incidence of the
chosen endpoint. This is based on a 10-25% incidence of clinical disease in the control population.
60 VA C C I N E P O L I C Y P R I C E - TA G S > T H E M A L A R I A P R O D U C T P I P E L I N E
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Scenario 2: The scientific community has an agreed Since the incidence of malaria infection is far higher than that
challenge model for blood-stage vaccines XLII of clinical malaria, vaccine trials require fewer patients to
show effect.
Scientific consensus has been reached on a challenge model
for blood-stage vaccines, which is as effective as the current
pre-erythrocytic challenge test. This allows ineffective blood- Clinical costs decrease to US$105 million, as trials for
stage candidates to be identified and knocked-out in Western pre-erythrocytic vaccines are downsized. Adult safety
labs and clinics, rather than being taken into Africa for testing trials remain the same size at around 1,000 subjects,
in patients. but child enrolment drops by 1,300 across Africa to
10,200 children. Although fewer sites are needed,
trials still take the same time, meaning that infant safety
This is a high-impact intervention, reflecting the high
trials still begin by 2012 and at the same low levels
proportion of blood-stage candidates in the current
(around 60 enrolments).
clinical and preclinical portfolios. Clinical development
costs drop to US$82 million. The number of candidates
tested in phase IIb in children drops from 13 to 9, and Scenario 5: Increased investment in basic malaria
child enrolments reflect this, dropping by 30% or nearly vaccine research
3,500 children, to a total of just over 8,000 children.
Troubled by the lack of a potent malaria vaccine, donors
increase their investment in basic research, resulting in a
Scenario 3: Improved co-ordination and investment tripling of the preclinical candidate portfolio.
decisions lead to fewer but better candidates
The donor community decides to increase co-ordination of Clinical development costs increase to US$124 million
trial design and trial endpoints to allow direct comparisons in the next 5 years, largely reflecting the increased number
between candidates. Based on this, and on co-ordinating of safety and challenge trials on potential new vaccine
their investment decisions, fewer candidates of each type are candidates. However, this has little impact on enrol-
carried forward, with poorer-performing candidates being ments, since most of these new candidates will not
killed earlier in the development process. Funding and incen- have reached field trials within our five-year timeframe.
tives are provided to encourage more industry input into
academic “research-based” preclinical projects, which helps
Scenario 6: Malaria incidence continues to drop
identify candidates likely to fail safety trials or which cannot
be made to realistic quantities. The combined impact is that Malaria rates continue to drop due to spraying programmes
attrition now matches the maximum attrition scenario. and widespread introduction of insecticide-treated nets (ITNs),
as well as ACT use and an increase in Intermittent Preventative
Therapy in infants and pregnant women. Malaria incidence at
Clinical costs drop to US$88 million, a saving of over
established trial sites drops to around 10% from a previous
US$20 million, as low-performing candidates are now
17% average; as a result, ever-larger enrolments are needed
knocked out early rather than being progressed into
to “power” trials to show decisive results. We note that this
field trials. Indeed, only 9 candidates make it to IIb trials
scenario is increasingly likely in future decades.
in children, meaning only 8,200 children in Africa now
need to be enrolled for vaccination - a 30% decrease on
the baseline model. Clinical costs increase to US$130 million, with child
enrolments pushed up by 40% to 16,500. The demands
on established trial sites means product developers
Scenario 4: Vaccine developers use malaria infection
increasingly need to look to new and less well-estab-
(rather than clinical disease) as their endpoint for pre-
lished sites in areas with higher malaria incidence. No
erythrocytic vaccines
products reach infant trials by 2012.
Rather than requiring vaccine trials to show a clinical impact
(i.e. fewer episodes of parasitaemia with fever), vaccine
developers use malaria infection as an endpoint for pre-ery-
throcytic vaccines (i.e. parasitaemia even without symptoms).
XLII We are referring to a theoretical challenge test for blood-stage vaccine candidates with the same attrition rate, cost, number of patients, phase duration and trial length as
the sporozoite challenge model used for pre-erythrocytic vaccines.
VA C C I N E P O L I C Y P R I C E - TA G S > T H E M A L A R I A P R O D U C T P I P E L I N E 61
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Figure 21. Vaccine policy price tags: Impact on global clinical development cost and child enrolments
Scenario 7: All trials are designed with lower efficacy In addition to the above scenarios, we model two additional
vaccine candidates in mind scenarios whose chief impact is on progress of the overall
global vaccine portfolio rather than primarily on cost and
Rather than designing trials for a vaccine with potential 50%
enrolment.
efficacy against first clinical episode, product developers
increasingly design trials around 30% efficacy, to ensure they Scenario 8: Regulatory authorities insist that a full
can demonstrate impact even if their vaccine is only a modest vaccine development protocol be followed
improvement on RTS,S (which showed 30% efficacy against
Regulatory authorities require that malaria vaccines be trialled
first clinical episode).
in Western volunteers before being trialled in Africa, and that
vaccines go through a full age de-escalation process, rather
Clinical costs nearly double to US$203 million, reflect- than “skipping” age groups at some stages. Back-to-back
ing the significantly larger trials that lower-efficacy trials are also discouraged both in the West and in the field
vaccines need to demonstrate impact. Although adult (e.g. the practice of running phase I safety trials into phase II
enrolment numbers remain the same, nearly 33,000 proof of concept trials).
children must be enrolled to demonstrate impact
(almost triple the baseline enrolment number), putting
The chief impact of this scenario is to substantially
an unprecedented strain on African trial sites. The
delay development of the overall vaccine portfolio,
global portfolio is slower to develop, reflecting the
with few projects reaching IIb trials in children and no
longer enrolment times needed to recruit these large
projects reaching safety trials in infants (see Figure 22).
numbers of subjects, and additional trial sites must be
Paradoxically, clinical development costs over the next
built up to meet enrolment targets.
five years decrease to US$105 million, since products
now take longer to move to the more expensive later
The relative impact of these scenarios on the total clinical stages. Likewise, African enrolments decrease
development cost of the global vaccine portfolio, as well as somewhat to around 1,000 adults and 8,700 children,
on child enrolments in Africa, is seen in Figure 21. with no infant trials or enrolments occurring by 2012.
62 VA C C I N E P O L I C Y P R I C E - TA G S > T H E M A L A R I A P R O D U C T P I P E L I N E
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Scenario 9: Regulatory authorities accept a simpler

vaccine development protocol
Regulatory authorities accept the simpler development High impact
protocols that some vaccine groups have been implementing. policy
Developers still need to conduct trials in the West before interventions
African trials, but combination trials at the Ia/IIa and Ib/IIb can save
level are the norm, as is the practice of “skipping” one or millions of
more age groups at the Ib and IIb phases (i.e. testing in only dollars and
three age groups at phase Ib and two at phase IIb).
thousands
of enrolments
The expedited regulatory pathway accelerates the in Africa
overall vaccine portfolio (see Figure 22). Five
candidate vaccines now reach trials in infants (the target
group), up from 1 candidate under the baseline
scenario. Clinical development costs increase to US$130
million, as more projects reach trials more quickly. Child
enrolments increase fractionally, with an additional
Figure 22. Cumulative number of candidates over a 5-year period
2,000 children enrolled across African trial sites.
to 2012 for the baseline, and simple and traditional development
However, infant enrolments increase substantially to
protocols
nearly 5,000 infants as products move more quickly into
phase lb/IIb safety, immunogenicity and preliminary
efficacy trials.
These collective scenarios highlight three points that policy-

makers and funders may want to be aware of:
No candidate in any of the modelled scenarios is able to
reach phase III trials in the five years to 2012. (We note
again, that RTS,S is excluded from these figures.)
The two most likely of these modelled scenarios (absent a
breakthrough technology) are decreasing malaria rates in
key trial areas, and lower rather than higher efficacy
vaccines for the foreseeable future. Both these scenarios
generate substantially higher enrolment burdens and costs
than the baseline scenario
Our modelling suggests that the highest impact policy
interventions in terms of expediting progress of the global
portfolio and decreasing projected cost and enrolment
burdens, are all decisions that are well within our reach. In
particular, improved coordination of global decision-
making, reaching agreement on a blood-stage challenge
model and streamlining the regulatory pathway.
* For the simple development protocol there is one Ib/IIb trial in children and a Ib/IIb
trial in infants followed by another IIb in infants/children
63
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SECTION
Based on our overall analysis and modelling, we recommend that stakeholders focus
their efforts on the three areas that are likely to deliver the greatest efficiencies and
the greatest improvement in overall product development:
1. Funding for malaria product development, the bulk of which will be for clinical
trial conduct and manufacturing
2. Consolidating the African network of malaria licensure trial sites. This will include
managing the flow of product trials to move sites up the growth trajectory, and
providing funding and management support to make the current network sustainable
3. Building on the Roadmap for Vaccine Technology recommendations, including with
respect to coordination, a blood-stage challenge model and regulatory issues.
5.1 FUND MALARIA PRODUCT A donor coordination exercise to collate information on their
DEVELOPMENT collective forward funding commitments would also allow
these to be assessed against likely costs, providing a clearer
It is clear from the findings outlined in Sections One to Four picture of the funding gap.
that, as matters now stand, malaria product development will
The above figures bring out two interesting - and promising -
require a substantial injection of funds over the next five years.
points. The first is that licensure trial sites, especially in Africa,
The total projected cost for clinical development and associ- are likely to receive an investment of well over US$120 million
ated manufacturing and toxicology of the global malaria to US$140 million in the coming years (around 60% of
product portfolio in the five years to 2012 is around US$668 clinical trial spend). This cash injection represents the single
million to US$746 million without offsetting forward funding best opportunity for strengthening, consolidating and
already given to RTS,S. The total outstanding cost once RTS,S positioning the African trial site network for the future.
forward funding is taken into account is US$561 million to However, these flow-ons are not automatic and much of their
US$639 million (see Fig. 23). The total outstanding cost breaks benefit will be wasted unless this investment is carefully
down into: managed at sponsor level and appropriately supported at
field level, as discussed below.
Around US$305 million to US$383 million for clinical trials
(a substantial proportion of which would go to developing The second point is the substantial opportunities that malaria
countries) product development represents for manufacturers, in partic-
Up to US$256 million for manufacturing (a substantial ular for CROs or partner firms who will be needed for
proportion of which would go to CROs, small pharmaceu- manufacture, toxicology, stability, process development and
tical firms and developing country manufacturers). the like. Some of this business will accrue to developing
country manufacturing firms (for example, MMVs partner-
These are ballpark figures. The numbers will increase if addi-
ships with Shin Poong in Korea and Ranbaxy in India) - with
tional preclinical research is funded and encouraged (these
this in itself being a positive flow-on. However, a great deal
projections assume 5 new vaccine candidates/year enter early
will also be available to U.S. and European CROs (both private
pre-clinical and 4 new drug leads/year enter clinical); and will
and public) and to small pharmaceutical firms (SMEs).XLIII
decrease if greater coordination is achieved by malaria
product developers so that fewer leads are progressed into
field trials. Indeed, if stakeholders successfully progress
current initiatives to encourage greater portfolio coordina-
tion, we are hopeful that funding requirements will be at the
lower end of our projections.
XLIII While larger pharmaceutical firms may benefit from the positive public and internal press they receive from contributing to these projects, they are unlikely to take a share
of these for-profit contracts since they generally operate their neglected disease divisions on a not-for-profit basis, providing their inputs as in-kind or at-cost.
64 R E C O M M E N D AT I O N S > T H E M A L A R I A P R O D U C T P I P E L I N E
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Figure 23. Projected cost for clinical development of the global malaria product portfolio to 2012*
* This is the direct (unadjusted)

cost of clinical development and
supportive manufacture and
toxicology for the malaria
product portfolio.
It is not the total cost of malaria
product development (i.e. basic
research, discovery, preclinical
studies, and roll-out costs are
excluded; as are general
overheads for development
groups).
5.2 CONSOLIDATE THE CLINICAL As noted previously, a vital tool in assisting consolidation of
TRIAL NETWORK this network is the anticipated large influx of product trial
funding over the next five years, and particularly in the next
Our assessment suggests that, if used efficiently, the overall two to three years. Over US$120 million to US$ 140 million
supply of malaria product licensure sites, including existing in vaccine trial funding alone will go to African sites; while
sites and those now being upgraded, is sufficient for the fore- the proportion of drug product funding, although more
seeable future. This means that policy makers can helpfully difficult to ascertain due to the involvement of private sector
shift their focus from building new licensure sites to sustain- players, would also be expected to be substantial. As noted
ing and growing the capacity of the existing licensure site above, if allocated and used wisely, this investment represents
network. the single best opportunity for strengthening capacity going
forward. However, project funding alone is not enough. In
This change in focus should provide a reliable network of
order to optimise the outcome of this anticipated influx,
around 23 malaria licensure sites in Africa by end 2008, with
additional measures will be needed, including: balancing
a further 14+ sites-in-waiting. If managed efficiently and
fluctuating project funding with long-term core funding
supported appropriately, this network of 23 sites should not
needs; ensuring sites have sufficient management skills to
only be able to deal with imminent product peaks but should
maximise outcomes from their project income; and using
be available from 2010-2011 onwards for large-scale non-
trials to move sites up the development trajectory.
malaria product trials in, for example, AIDS, TB, rotavirus,
pneumonia, meningitis and diarrhoeal illnesses. (The 5.2.1 BALANCED FINANCIAL SUPPORT
exception is Nigeria, where new vaccine sites may be needed
Trial sites have two main sources of income: untied core
to fill the gap, perhaps through upgrading existing drug trial
funding and overheads on project funding. Together, these
sites or high-quality research sites with large-scale trial
funds need to cover average site overheads of around
potential.)
20-30% as well as provide a surplus to invest in growth (e.g.
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baseline epidemiological studies to support expansion into a based on an existing World Bank endowment fund for
new disease area). In the absence of sufficient funding, sites environmental conservation (the Eastern Arc Mountains
cannot maintain core staff, facilities and services such as DSS, Conservation Endowment Fund, Tanzania: http://easternarc.
and most certainly cannot diversify. or.tz/index.html)
Implementing cost recovery systems:
It is a common fallacy that trial sites can become sustainable
• Charging new projects for use of existing infrastruc-
by learning to manage themselves better, by scheduling trials
ture. This is somewhat limited in usefulness, however,
more efficiently or by diversifying their funding and disease
since it tends to make the site relatively more expensive
base. This is simply not true, or at least not as things now
and therefore less attractive compared to other sites in
stand. In practice, since project overheads are consistently
multi-centre trials
well below real site overheads, additional trials simply leave
• Charging fees to Western institutions who train their
sites running on the spot or even falling behind. Mature sites
staff and students at the trial site, or who use the site’s
have managed this dilemma with the help of long-term core
laboratories for training purposes
funding from Western funders, however they represent only
• Leverage site infrastructure e.g. one site opened an
one-quarter of the site network. The remaining sites - the
internet café, using the profits to subsidise the cost of
new and young sites that represent the future for malaria
satellite internet access needed for product trials.
trials, and increasingly for other disease trials - do not have
this luxury.
5.2.2 MANAGEMENT SUPPORT
If we are to reap the benefits of the now substantial invest-
Young and new licensure sites need more than funding. They
ments made in creating this new site network, then we need
also need the skills to efficiently manage multiple trials and
to make sure it is viable. Possible options to provide a sound
the fluctuating funding streams these generate. Some sites
financial underpinning for the site network (particularly new
have difficulty planning for growth because they are unable
and young sites) include:
to clearly define their running costs, project overheads,
Preferentially allocate licensure trials (and product-linked capital costs, recurrent costs etc. Many young and new sites
upgrades) to the 23 identified sites that form the hub of do not distinguish between project income, which is largely
the African malaria product trial network consumed by the project itself, and core income, which is
Ensure that capacity building is linked to trials (IPTi, entirely available to the site to invest. Only one or two of the
product trials etc.) rather than conducted in isolation 20+ sites interviewed had conducted a full economic costing,
Provide sites with a mix of project funding and reliable with most having only a rough idea of what their real running
longer-term core funding costs might be. Although this is not unusual (many Western
Provide sufficient core funding for at least five years to institutions are in a similar situation) it is vital for trial sites
support all sites in the 23-strong network, perhaps that rely on project margins for their survival.
starting with the young and new “all purpose” licensure
Trial scheduling is also a difficulty for many sites, with lack of
sites (mature sites already receive core funding).XLIV Where
experience making it difficult to judge how many trials they
possible, this should include an element of local or
might or might not be able to manage simultaneously. Many
national government funding as well as external donor
sites appeared to overestimate the number of patients they
funding
could readily access (particularly infants), tending to rely on
If there is a reluctance to provide core funding, then donors
DSS coverage or birth statistics as a guide to likely enrol-
and product developers will need to provide overheads at
ments. Younger sites also had less experience in segmenting
the level suggested necessary by full economic costing
their available populations (e.g. a child drug trial in one area;
(perhaps 20-30% on top of project costs)
an infant vaccine trial in another), and in expanding and
Make project grants more efficient, including through: less
shrinking their patient “draw” area according to need.
onerous reporting requirements; provision for more
Additional hurdles were large staff fluctuations, difficulties in
flexible use of resources across projects; and a less bureau-
finding and retaining experienced core staff, and lack of flex-
cratic approach to project contracts.
ibility in deploying core staff between trials.
Other options suggested or implemented by sites included:
A number of initiatives currently aim to provide trial sites in
An “endowment fund” supported by bilateral or multilat- Africa with some of these management skills. For example,
eral donors to cover core costs for trial sites. This idea was the Bill & Melinda Gates Foundation-funded Malaria Clinical
XLIV The “young” all-purpose sites (HAS, Gabon; KCCR/SMS, Ghana; KHRC, Ghana; NIMR, Tanzania; Navrongo, Ghana; CNRFP, Burkina Faso); and the new sites now being
upgraded to “all purpose” standards (Blantyre, Malawi; CDC-Kemri, Kenya). CNRFP, Burkina Faso also needs to be assessed for infrastructure capacity
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Trial Alliance (MCTA) aims to strengthen the capacity of are far easier to manage and co-ordinate, therefore drug
African trial sites, focussing on a business-model approach to centres are less likely to need this level of support). The
malaria drug and vaccine trials. The MCTA facilitates GCP and CTF would have trained core staff who understand regu-
data management training; provides management and latory needs, quality issues etc. and can coordinate,
financial training; advises on infrastructure and growth supervise and manage across all trials e.g. Principal
needs; develops shared protocols, tools and networked Investigators (PIs), a Medical Officer, regulatory Data
knowledge; facilitates the development of long term business Management etc.
planning, links clinical trial site infrastructure with product • This group would prepare standardised training
development; and offers mentoring and leadership pro- manuals and standard operating procedures (SOPs);
grammes to research facility managers across Africa. MCTA supervise GCP-GLP-Quality Assurance/Quality Control
has also provided one-off investments in some circumstances, training and maintenance; manage allocation of staff
although its main goal is as an enabler of trial site develop- and resources (such as vehicles) across trials; manage
ment rather than a funder. Currently, the MCTA supports 14 trial scheduling and planning; and be trained in the
sites in Africa. business and financial skills necessary to run the overall
trial centre. A CTF not only provides more efficient and
The EDCTP also offers training and support to trial sites in the
flexible trial management, it also decreases core costs
following areas: project management, financial procedures,
(e.g. through fungibility of resources). CTFs could also
GCP, leadership, ethics and regulatory affairs as well as
potentially be networked across all sites, along the lines
providing opportunities for African scientists for career devel-
of the MCTA approach.
opment. However, to date this training appears to have
• We note that some sites already have a CTF (e.g.
focussed more on technical clinical trial skills and career
USAMRU-K) or are already planning to use MCTA
development than on management skills, with the EDCTP
funding to set up a CTF (e.g. Kilifi, Kenya, which specif-
funding a number of workshops and training sessions on
ically noted a CTF as a way to avoid “reinventing the
ethics and GCP, as well as funding PhD scholarships, career
wheel each time” and to work in a way that was
development fellowships and senior fellowships for African
“much faster and more efficient”).
researchers. AMANET also has a strategic goal, ”To strength-
Fund a formal on-site staff training programme for all new
en the network and capacity of R&D in Africa and African
and young licensure sites that do not yet have one (on-site
institutions for undertaking intervention trials to develop effi-
training is a hallmark of successful mature trial sites)
cacious, affordable and accessible malaria intervention
Develop a formal mentoring system between mature sites
tools.”13 Again, this has a technical rather than management
and young or new African licensure sites (or, as one site
focus, with a focus on training in ethics, GLP, GCP, study
Director described it, a system of “sister sites”) as well as
design, data management, molecular biology and immunolo-
with Western institutions.
gy. AMANET supports 4 sites in Africa with direct funding,
• This could involve mentoring by senior PIs and/or man-
although all African sites are welcome to attend AMANET
agement staff from experienced sites, as well as
training workshops.
cross-training or exchange of personnel. For example,
Possible measures to provide new and young sites with Navrongo (a site with a large and well established DSS)
greater support in developing the necessary management helped CNRFP to set up their own DSS, including
and financial skills (as opposed to technical clinical trial skills) training a seconded CNRFP demographer.
include: • We note that the EDCTP has recently launched a call
for a mentoring system. This involves four regional
Funders could support expansion of the MCTA to all 23
networks in Africa, each comprising at least three com-
sites in the African malaria network
plementary “nodes of excellence” (possibly including
EDCTP and/ or AMANET could provide additional manage-
one Western institution) and a fourth centre with less
ment and financial training to sites they support, including
experience/capacity, which they would mentor. The
sites outside the MCTA network. (We note that discus-
EDCTP will provide seed funding of €10 million to set
sions have also been held between MCTA and EDCTP
up and consolidate the original four networks, and will
regarding possible collaboration, and this remains an
seek funding from others to expand these.
option for the future.)
A Clinical Trials Facility (CTF) could be funded at each of
the 15-16 licensure standard vaccine centres (drug trial
centres are excluded from this proposal since drug trials
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A closely linked proposal was to develop a formal 5.2.3 MANAGE TRIAL FLOWS
programme of training attachments with experienced
Allocation of upcoming malaria licensure trials across the trial
African licensure sites, Western clinical trial institutions
site network may have very different outcomes. At worst,
and/or Western pharmaceutical firms. Again, some sites
trials will be allocated without reference to the bigger picture,
already have such a programme, for example the MRTC in
allowing specialist large-scale sites to be tied up with non-
Mali routinely seconds trainees to GSK (using TDR grants)
licensure trials while less experienced sites are forced to
and to the University of Alabama; and will generate five
expand into large licensure trials at rates that push their
fully trained PIs in 2007 alone. The EDCTP similarly
capacity and integration to the limit. At the other end of the
provides €1 million per year to companies such as GSK to
spectrum, efficient trial allocation will allow upcoming
train African trial monitors through in-house attachments
product peaks to be managed smoothly, while ensuring that
with the company; and just under €600,000 for Western
new and young sites are moved along the development tra-
institutions such as the Vienna School of Clinical Research
jectory towards full maturity.
(VSCR), Austria, to provide sites with GCP training.
However, although valuable, these initiatives are inde- In general, the site network is likely to work best if we move
pendent and uncoordinated rather than being part of a from the current model of six “super sites” that can enrol
formal support package available to all new and young thousands of patients in simultaneous trials to a more flexible
licensure sites. model of 15-20 “all purpose” sites able to manage two or
more trials of 400-800 subjects each. This approach has the
Table 14. Site growth proposal advantages that it:
SITE TYPE GROWTH STRATEGY GROWTH CATALYST FUNDING
Mature “all purpose” licensure sites Continue as central plank of Normal business Have committed core funding
product trials Have MCTA support
Enlist for mentoring/ training of (except MRCT in Mali)
newer sites
Mature “all purpose” licensure sites Expand existing enrolment networks Large-scale malaria vaccine trials (e.g. Limited or no core funding
(health centres / prenatal clinics / phase IIb, III) Have MCTA support (except Navrongo)
vaccination centres) Higher-tech aspects of phase IV trials
>
Management support (MCTA style)

Consider core funding
Training / secondments / links with
mature sites
Expand DSS to new areas
Young “all-purpose” licensure sites Conduct epidemiological baseline
studies for other diseases
Vaccine licensure sites Start with small vaccine trials and Small vaccine trials (phase Ib) Three sites have MCTA, NIH or
increase Label extension drug trials AMANET support
>
Management support (MCTA style)

Training / secondment / links with young Consider core funding
and mature vaccine sites
Drug licensure sites
Quality research sites with no Large-scale observational trials Lower-tech phase IV observational
licensure experience Can move up to small scale drug trials if studies
more sites needed IPTi, IPTp
“Assisted” drug trials
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Encourages organic growth, allowing site staff to develop This could include both experienced staff (a form of
their management and trial skills, and their connection reverse brain drain?) and a pool of more junior staff to
with local communities mitigate large employment swings at sites.
Spreads risk associated with variable malaria seasons,
5.2.6 FUTURE PLAN
enrolment failures and management issues
Makes it easier to manage anticipated peaks and slumps In the next tranche of our research, we plan to work with trial
in drug and vaccine enrolments over the next 5 years sites and funders to seek their views on policies, incentives
without entering a “boom and bust” cycle and coordinating principles to improve management of trial
Provides a broad network of sites suitable to conduct flows and to support the trial site network, and to discuss ini-
larger trials in malaria or other disease areas in the future tiatives they are now taking or planning in this area. Based on
e.g. pneumonia, HIV, diarrhoeal diseases. these discussions, we hope to develop a range of proposals
for consideration by the malaria community that could help
This transition to a network of all-purpose sites appears to be
achieve these goals.
well underway. An example of future trial allocation that
could expedite this growth is seen in Table 14.
5.2.4 PHASE IV TRIALS 5.3 BUILD ON THE MALARIA

Coordinate the proposed Phase IV Consortium - ACT VACCINE TECHNOLOGY
Consortium - MIP - WHO/TDR trials to remove duplications ROADMAP
and maximise information gained from each. We note that
The overall goal of policy-makers and funders in the malaria
the Gates Foundation, as a potential funder of several of
vaccine field is to deliver fewer but better vaccine candidates,
these initiatives, is now working to improve coordination in
and to create policy settings that facilitate and support this
this area
goal. Measures to achieve this, beyond provision of funding
Urgently review the possibility of 3-arm head-to-head phase
and trial sites, are set out in the Roadmap.
IV drug trials
Distinguish between more sophisticated phase IV trials In addition to supporting these Roadmap recommendations,
that might best be done at licensure sites, and lower-tech we highlight a number of proposals that may complement or
observational trials that might best be done at non-licensure build on them. Our recommendations fall into three main
sites. Use these distinctions to allocate trials efficiently, as groups: measures to improve innovation; measures to reduce
noted above. technical barriers; and policy measures to improve coordina-
tion of trial results and portfolios, and expedite regulatory
5.2.5 OTHER POSSIBILITIES FOR approval of new vaccines.
CONSIDERATION
5.3.1 GREATER INNOVATION
Set up or build on central information sources on all
(BETTER CANDIDATES)
upcoming licensure and phase IV product trials
Develop an agreed minimum site audit template, so that Increase funding for basic malaria vaccine research, as
site audits can be more readily compared and/or shared modelling suggests that the overall clinical vaccine
(rather than necessarily being repeated) portfolio may otherwise decrease over time. For example,
Develop a shared Trial Site Audit service (perhaps CRO the BioMalPar projects at The Wellcome Trust Sanger
style?), which would also decrease high levels of repeat Institute and Institut Pasteur; and the Gates Grand
auditing at sites (up to five audits at some sites); and Challenge MalariaGen at University of Oxford.
perhaps to review site standards over time (e.g. microscopy Support novel malaria technology platforms
services). In this context we note a proposal tabled at the • Promote greater pairing of industry innovators with
2007 MALVAC meeting that the EDCTP undertake detailed public malaria researchers to develop joint projects
mapping of licensure sites, building on surveys already (e.g. the NRMC/MVI/GenVec collaboration)
being done by the Bill & Melinda Gates Foundation, • Develop incentives or policies to encourage relation-
INDEPTH/MCTA, AMANET, and earlier EDCTP work ships between public and academic vaccine developers
through the Developing Country Coordinating Committee and industrial facilities. These incentives could cut
Develop an African-based CRO to provide contract staff learning curve times, ensure expertise is maintained
for clinical trials e.g. trial site monitors or data managers. and facilitate technology transfer (e.g. following along
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the lines of the Seeding Drug Discovery14 scheme Improve access to potent adjuvants, with several
funded by the Wellcome Trust, which makes academic initiatives now underway, including:
drug discovery grants conditional on up-front industry • An MVI initiative aimed at making several novel
participation in technical and management areas) adjuvants available to test in malaria vaccines for the
• Develop biotech-relevant policies and incentives for first time. These include Novartis’ MF59, sanofi
groups trying high-risk, high-innovation approaches pasteur’s E6020, and Dynavax’s ISS
(companies cite cash-flow; opportunities for platform • The Wellcome Trust recently announced a new funding
testing etc.). We will publish a more detailed report in scheme aimed at supporting further identification and
late 2007 outlining potential biotech incentives to development of adjuvants for vaccines being
promote vaccine innovation in Europe XLV developed, with a focus on public-private collabora-
• Design incentives to encourage biotechs wishing to tions. This initiative has the potential to stop good
test out novel technologies or constructs to collaborate constructs being terminated prematurely because they
with well-established product-developers who have the are paired with comparatively weak adjuvants.
technical skills and experience to make the technology
feasible.
5.3.3 REMOVE POLICY BARRIERS (FEWER
CANDIDATES)
5.3.2 REDUCE TECHNICAL BARRIERS
(BETTER CANDIDATES) As spelt out in the Roadmap and noted above, funders would
greatly benefit from a more closely co-ordinated approach to
Provide industrial assistance to public and academic trial design and measurement to help identify potential
groups without industrial capacity winners among vaccine candidates. As much progress is
• Develop a public inventory of accessible public and being made on these issues (see Table 1), we restrict ourselves
private vaccine manufacturing facilities (e.g., the WRAIR to commenting on Roadmap recommendations highlighted
Pilot Lot Facility, developing country manufacturers and by our own findings, and on new measures that could build
contract manufacturers); with ratings provided on on these.
capacity, quality, cost, type of technology, availability
etc. of each. This approach has the benefit of generat-
ing repeat business for high-rated listed firms, thereby
overcoming problems associated with spasmodic
involvement (e.g. lack of commitment; lack of malaria
know-how; steep learning curves for one-off firms and
newcomers). MVI is considering such an inventory
• Provide a funding stream for contracted industry input
to public candidates early in the preclinical process,
ideally by leveraging existing manufacturing expendi-
tures. For example, see our earlier proposal for an
Industry R&D Facilitation Fund (IRFF).XLVI
• Alternatively, as proposed in the Roadmap, a public or
semi-industrial production facility dedicated to devel-
oping and producing sufficient material for phase I and
phase II trials could be built up, with a view to transfer-
ring the technology to large pharmaceutical companies
or developing country manufacturers in the later stages
of development (e.g. in a similar manner to that of a
proposed Strategic Vaccine Facility for the UK15). In
general, though, it seems inefficient to create a new
public facility rather than improving use of and access
to substantial existing public and private capacity.
XLV This report is a collaboration with IAVI

XLVI The IRFF proposal is outlined in Moran M, Ropars AL, Guzman J, Diaz J and Garrison C. The new landscape of neglected disease drug development. London School of
Economics and The Wellcome Trust. September 2005: 68-73. http://www.thegeorgeinstitute.org/shadomx/apps/fms/fmsdownload.cfm?file_uuid=F2B06396-EEA0-851E-
3049-C9A030AEDE0F&siteName=iih .
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Develop standardised assays, reagents and protocols; and • Strengthen the capacity of National Regulatory
secure agreement to use these Authorities in developing countries to assess regulatory
dossiers independently. For example, initiatives such as
• Secure agreement on a human challenge model for
that instigated by WHO, with the development of the
blood-stage vaccines, including the associated scientif-
AFRO Vaccine Regulators Forum (AVAREF), funded by
ic and ethical questions. Modelling suggests this is one
the EDCTP and the Netherlands-African Partnership for
of the highest impact interventions that policy-makers
Capacity Development and Clinical Interventions Against
and scientists can deliver, in terms of reducing
Poverty-related Diseases (NACCAP)
enrolment burden in Africa and development costs
• Establish clear guidelines for ethical approval of vaccine
• Improve co-ordination across Western challenge
trials and reduce duplication in the Institutional Review
centres (which conduct phase IIa challenges of pre-ery-
Board (IRB) process (a particular problem for multi-
throcytic vaccines) to enable comparisons of trial
centre trials). We note that some work on coordinating
results; particularly with respect to standardising
groups in Africa is underway, for example, through
operating procedures and clinical trial protocols (e.g.
AVAREF. AMANET has also identified areas where it
parasite strain used, diagnosis of malaria by PCR or
could facilitate the progress of IRBs, in conjunction with
thick film blood smear, number of infective bites, defi-
the African Union (AU), NEPAD and WHO
nition of patency periods)
• Support African IRBs to develop increased capacity for
• Provide add-on funding for immunological studies
ethical review.
alongside trials to allow results to be cross-referenced
against each other and against laboratory predictors
(getting value from failure as well as from success)
• Provide additional resources to WHO to assist them to
achieve agreement on use of standardised assays,
reagents and protocols (to the extent possible) as
quickly as possible.
Develop shared vaccine ranking criteria; and reduce ineffi-
ciency and duplication resulting from working in isolation
• Prioritise co-ordination of global malaria vaccine R&D
choices and technologies, as modelling identifies this
as a particularly high-impact activity in terms of cutting
costs and enrolments
• Provide additional resources to WHO to assist them in
developing and gaining agreement on a co-ordinating
framework for the global vaccine portfolio.
Simplify regulatory processes
• Establish clear guidelines for the regulatory approval
process to allow the global malaria vaccine portfolio to
move forward more quickly, including guidelines on
omission of some steps in the age de-escalation
process (for example, skipping IIb trials in adults), and
on the practice of combining phases or running them
contemporaneously (for example, running phase lb/llb
trials in combination, as opposed to conducting them
separately)
ANNEXES > THE MALARIA PRODUCT PIPELINE 71
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ANNEXE
ANNEXE 1A. MALARIA DRUG PROJECTS (DECEMBER 2006)
CURRENT MALARIA DRUG PORTFOLIO IN PRECLINICAL OR CLINICAL DEVELOPMENT (DECEMBER 2006)

PROJECT LEAD DOER STAGE PARTNERS
1 SAR97276A/T3 sanofi aventis Preclinical University of Montpellier

2 Isoquine MMV Preclinical University of Liverpool, GSK
3 4 (1-H) pyridones GSK 932121 MMV Preclinical GSK
4 PS-26 Jacobus Pharmaceutical * Preclinical
5 Novel tetracyclines Paratek Pharmaceuticals * Preclinical
6 Novel trioxanes Johns Hopkins University * Preclinical
7 Tafenoquine (for P. vivax) MMV Preclinical GSK, WRAIR
8 Tinidazole-primaquine (for P. vivax) WRAIR Preclinical
9 AQ13 Tulane University I
10 Ferroquine-artesunate sanofi aventis II University of Sciences & Technologies of Lille
11 Fosmidomycin-clindamycin University of Tübingen II Jomaa Pharmaka
12 IV artesunate WRAIR II Sigma Tau, MMV**
13 Azithromycin-chloroquine Pfizer II/III
14 Intrarectal quinine sanofi aventis III
15 Chlorproguanil-dapsone-artesunate MMV III WHO/TDR, GSK, University of Liverpool
16 DHA piperaquine MMV III University of Oxford, Sigma Tau, Holley Kin, Chongqing Holley
17 Artemether-Lumefantrine MMV III Novartis
(Coartem Dispersible)
18 Pyronaridine-artesunate (Pyramax) MMV III University of Iowa, Shin Poong Pharmaceutical Co.
19 Artesunate-mefloquine DNDi Registration University of Oxford, Mahidol University, Universiti Sains, Far
Manguinhos, WHO/TDR, Médecins Sans Frontières
20 Rectal artesunate WHO/TDR Registration

21 Artesunate-amodiaquine DNDi, sanofi aventis IV CNRFP Burkina Faso, University of Oxford, Tropival/University
of Bordeaux, Universiti Sains, WHO/TDR, Médecins Sans
Frontières
* NIH-funded projects
** MMV is sponsoring a phase II paediatric study.
72 ANNEXES > THE MALARIA PRODUCT PIPELINE

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ANNEXE 1B. PRE-CLINICAL MALARIA VACCINE PROJECTS (NOVEMBER 2006)
PROJECT FORMULATION LEAD DOER PARTNERS
BLOOD-STAGE VACCINES
AMA-1
AMA-1 FVO (FMP009) E. coli/AS01B WRAIR GSK Biologicals, USAID
1 AMA-1 FVO (FMP009) E. coli
AMA-1 FVO (FMP009) E. coli/AS02A WRAIR GSK Biologicals, USAID
2 AMA1-C2 AMA-1 FVO, AMA-1 3D7, AMA-1 L32 NIH (MVDB) WRAIR Pilot Bioproduction Facility,
P. pastoris/Alhydrogel + CPG7909 Coley Pharmaceutical Group
MSP-1
3 MSP-1 19 D. melanogaster MSP-1 19 D. melanogaster NIH, Hawaii Biotech Inc
4 MSP-1 42 D. melanogaster MSP-1 42 D. melanogaster NIH, Hawaii Biotech Inc
5 MSP-1 42 E. coli MSP-1 42 E. coli ICGEB
MSP-1 42 FVO (FMP010) E. coli/AS01B WRAIR GSK Biologicals, USAID
6 MSP-1 42 FVO (FMP010) E. coli
MSP-1 42 FVO (FMP010) E. coli/AS02A WRAIR GSK Biologicals, USAID
7 MSP-1 FUP baculovirus MSP-1 FUP baculovirus/QS-21 NIH, University of Hawaii
8 MSP-1 19 baculovirus MSP-1 19 baculovirus Institut Pasteur
AMA-1 and MSP-1 combinations
BSAM-1 (PpAMA-1 C1+ EcMSP-1 42-C1) NIH (MVDB) WRAIR Pilot Bioproduction Facility,
9 BSAM-1
Alhydrogel + CPG 7909 Coley Pharmaceutical Group
10 PfAMA-1/MSP-1 fusion P. pastoris PfAMA-1/MSP-1 fusion P. pastoris EMVI BPRC, Mill Hill
11 Adeno 5 (AMA-1, MSP-1) Adeno 5 (AMA-1, MSP-1) PATH MVI GenVec, NMRC
MSP-1 and EBA-175 combinations
12 MSP-1 19/EBA-175 F2 E. coli MSP-1 19/EBA-175 F2 E. coli EMVI ICGEB, Bharat Biotech Int
MSP-2
MSP-2 3D7+ MSP-2 FC29 E. coli/Montanide PATH MVI La Trobe University, Gropep Ltd, CSL,
13 MSP-2 3D7+ MSP-2 FC29 E. coli
ISA 720 Royal Brisbane Hospital
14 MSP-2 Long synthetic peptide MSP-2 Long synthetic peptide University of Lausanne STI
MSP-4
15 MSP-4 E. coli MSP-4 E. coli/Montanide ISA 720 PATH MVI Monash University, CSL
MSP-5
16 MSP-5 E. coli MSP-5 E. coli/Montanide ISA 720 PATH MVI Monash University, CSL
GLURP
17 GMZ-1 L. lactis GMZ-1 L. lactis/Aluminium Hydroxide EMVI SSI
EMP-1
18 PfEMP1 DBL1 -TM-AS recombinant PfEMP1 DBL1± Karolinska Institute Swedish Institute for Infectious
Semliki Forest Virus (SFV) Disease Control, Institut Pasteur,
University of Edinburgh, Seppic
Other Antigens (unspecified)
19 10 new peptides 10 new peptides University of Lausanne STI, Institut Pasteur
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PROJECT FORMULATION LEAD DOER PARTNERS
MULTISTAGE VACCINES
CSP and AMA-1 Combinations
20 M3V-AdM-PfCA (Ad prime/MVA boost) 1 M3V-AdM-PfCA (Ad prime/MVA boost) NMRC GenVec
21 M3V-DAd-PfCA (DNA prime/Ad boost) M3V-DAd-PfCA (DNA prime/Ad boost) NMRC GenVec, Vical
22 M3V-M-PfCA (MVA alone)1 M3V-M-PfCA (MVA alone) NMRC
Multiple Antigens
23 Adeno 5 Adeno 5 (CSP, CelTOS, LSA1, MSP1, AMA1) PATH MVI GenVec, NMRC
24 FALVAC FALVAC-1A multi-epitope recombinant protein CDC Bharat Biotech, National Institute of
Immunology New Delhi, Protein
Sciences Corporation
25 Mulitepitope string DNA Mulitepitope string DNA NIH, Pharmexa-Epimmune
26 P. falciparum synthetic GPI toxin Synthetic GPI toxin NIH, Ancora Pharmaceuticals WEHI, Swiss Federal Institute of
Technology
PRE-ERYTHROCYTIC VACCINES
TRAP
27 Adenovirus / MVA ME-TRAP Adenovirus / MVA ME-TRAP University of Oxford MRC
Attenuated sporozoite
28 Radiation-Attenuated sporozoites Radiation-attenuated sporozoites Sanaria, Inc.2 PATH MVI NMRC, NIH, Protein Potential
29 Knock-Out Sporozoites Knock-out sporozoites SBRI, WRAIR GCGH
LSA-3
LSA-3 L. lactis/Alhydrogel Institut Pasteur, European Henogen, Confarma, University of
Commission Nijmegen
30 LSA-3 L. lactis
LSA-3 L. lactis/Montanide ISA 720 Institut Pasteur, European Henogen, Confarma, University
Commission of Nijmegen
31 LSA-3 mix lipo LSA-3 mix lipo Institut Pasteur Henogen, Bachem, Confarma
Green-highlighted rows are preclinical projects, which were not included in the WHO Rainbow list
1 These projects are not currently funded by the NMRC, but are included as viable vaccine candidates since they represent potential future funding needs

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ANNEXE
ANNEXE 1C. CLINICAL MALARIA VACCINE PROJECTS (NOVEMBER 2006)
PROJECT PROJECT FORMULATION FORMULATION LEAD DOER PARTNERS

STAGE PHASE
AMA-1
1 PfAMA-1 FVO Ia PfAMA-1 FVO P. pastoris/DDA/TDB Ia EMVI BPRC, SSI, AMANET

P. pastoris PfAMA-1 FVO P. pastoris/Aluminium Hydroxide Ia EMVI BPRC, SSI, AMANET
PfAMA-1 FVO P. pastoris/AS02A Ia EMVI BPRC, GSK Biologicals, AMANET
PfAMA-1 FVO P. pastoris/Montanide ISA 720 Ia EMVI BPRC, Seppic, AMANET
2 AMA-1 3D7 (FMP2.1) Ib AMA-1 3D7 (FMP2.1) E. coli/AS01B Ia/IIa PATH MVI, GSK Biologicals, USAID
E. coli WRAIR
AMA-1 3D7 (FMP2.1) E. coli/AS02A Ib WRAIR GSK Biologicals, USAID, University of
Maryland, MRTC
3 AMA-1 C1 lb/IIb AMA-1 C1 P. pastoris/ ISA720 Ia NIH (MVDB) PATH MVI, WRAIR Pilot Bioproduction Facility,
P. pastoris Amgen Inc.
AMA-1 C1 P. pastoris/Alhydrogel + CPG 7909 Ia NIH (MVDB) PATH MVI, WRAIR Pilot Bioproduction Facility,
Coley Pharmaceutical Group
AMA-1 C1 P. pastoris/Alhydrogel lb/IIb NIH (MVDB) PATH MVI, WRAIR Pilot Bioproduction Facility,
MRTC
MSP-1
4 MSP-1 42 C1 E. coli Ia MSP-1 42 C1 E. coli/Alhydrogel Ia NIH (MVDB) PATH MVI, WRAIR Pilot Bioproduction Facility,
Amgen Inc.
MSP-1 42 C1 E. coli/Alhydrogel + CPG 7909 Ia NIH (MVDB) PATH MVI, WRAIR Pilot Bioproduction Facility,
Coley Pharmaceutical Group
AMA-1 & MSP-1 combinations
5 PfCP-2.9 P. pastoris Ia PfCP-2.9 P. pastoris/Montanide ISA 720 Ia PATH MVI Shanghai Wanxing Bio-Pharmaceuticals,
Shanghai Second Military Medical University,
Shanghai Changhai Hospital, WHO/IVR
MSP-3
6 MSP-3 LSP poly-peptide Ib MSP-3, LSP poly-peptide/Aluminium Hydroxide Ib Institut University of Lausanne, Sedac Therapeutics,
Pasteur, EMVI AMANET, CNRFP
MSP-3 & GLURP combinations
7 GMZ-2 L. lactis Ia GMZ-2 L. lactis/DDA/TDB Preclinical EMVI SSI, AMANET
GMZ-2 L. lactis/Aluminium hydroxide Ia EMVI SSI, AMANET
EBA-175
8 EBA-175 RII-NG P. pastoris Ia EBA-175 RII-NG P. pastoris/Aluminium Ia NIH SAIC (Science Applications International
Phosphate Corporation), Protein Potential, Cambrex
SERA
9 SE36 E.coli Ia SE36 E. coli Ia Osaka Med Biotech Laboratories, Biken
University Foundation, WHO/TDR
MULTISTAGE VACCINES
CSP and AMA-1 combinations
10 PEV3A IIa PEV3A IIa Pevion Swiss Tropical Institute, Basel University, Swiss
Biotech Innovation Promotion Agency
11 M3V-Ad5-PfCA (Ad alone) Ia/IIa M3V-Ad5-PfCA (Ad alone) Ia/IIa NMRC GenVec, USAID
CSP
12 RTS,S IIb RTS,S/AS01(B/E) IIb PATH MVI, WRAIR
GSK Biologicals
RTS,S/AS02 (A/D) IIb PATH MVI, WRAIR
GSK Biologicals
13 Adenovirus 35 CS Ia Adenovirus 35 CS Ia NIH, Crucell
14 DNA/MVA CSP1 Ib PfCSP DNA/MVA CSP (MVA.CSO) prime-boost Ib NMRC University of Oxford, NIH
TRAP
15 FP9/MVA ME TRAP IIb FP9/MVA ME-TRAP IIb University of Gates Malaria Partnership, KEMRI
Oxford
Multiple Antigens
16 FP9/MVA polyprotein Ia/IIa FP9/MVA polyprotein Ia/IIa EMVI University of Oxford, Wellcome Trust, MRC
Rows coloured grey are listed as preclinical in the WHO Rainbow list (Dec 2006), but have now reached clinical trials
Green highlighted rows are “new” clinical projects, i.e., those which are not included in the WHO Rainbow list
1 Although this combination is not being developed as a final product, it is included as it has generated trials and expenses
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ANNEXE 1D. EXCLUDED PRECLINICAL VACCINE PROJECTS LISTED IN THE WHO RAINBOW LIST
PROJECT NAME LEAD DOER, PARTNERS REASON FOR EXCLUSION
1 LSA-3 long synthetic peptide EMVI, Institut Pasteur, Dictagene Inactive
2 LSA-1 adenovirus vectored (LSA-NRC) WRAIR, Crucell Inactive
3 LSA-1 D. melanogaster expressed NIH, Hawaii Biotech Inactive
4 Region II Duffy Binding Protein E. coli expressed ICGEB P. vivax-specific vaccine - outside the scope of this project
5 EBA-175 F1 E. coli-expressed ICGEB Inactive
6 EBP2/BAEBL P. pastoris-expressed NIH, Entremed Inactive
7 RAP-2 E. coli-expressed MVI, QIMR, CSIRO, Progen Inactive
8 PfEMP-1 E. coli, P. pastoris, baculovirus-expressed, different domains EMVI, Various EU groups Inactive
9 MSP-1 3D7 + FCB1 recombinant full length WRAIR, University of Heidelberg Inactive
10 MSP-1 3D7 recombinant full length WRAIR, University of Heidelberg Inactive
11 MSP-1 FCB1 recombinant full length WRAIR, University of Heidelberg Inactive
12 MSP-1-42/EBA-175 chimera E. coli expressed WRAIR Inactive
13 MSP-1 42 FVO transgenic goat-expressed NIH, GTC Biotherapeutics, SAIC Inactive
14 MAEBL NIH, Notre Dame University In early research
TRANSMISSION-BLOCKING VACCINES
15 PvS28 DNA immunisation JHU Outside the scope of this project
ANNEXE 1E. EXCLUDED CLINICAL VACCINE PROJECTS LISTED IN THE WHO RAINBOW LIST
1 CSP DNA immunization NMRC Inactive
2 CSP Long synthetic peptide Dictagene/University of Lausanne Inactive
3 HBCAg-CSP VLP Malarivax, Apovia Inactive
4 RTS,S/AS02 and Modified Vaccinia Ankara (MVA) CSP University of Oxford, GSK Biologicals Inactive
5 LSA-1 E.coli expressed/AS02A (LSA-NRC) GSK Biologicals, WRAIR Inactive
6 LSA-1 E.coli expressed/AS01B E (LSA-NRC) GSK Biologicals, WRAIR Inactive
7 Modified Vaccinia Ankara (MVA) CSP + LSA-1 University of Oxford, WRAIR Inactive
8 Fowl Pox 9 CSP +LSA-1 University of Oxford Inactive
9 MSP-1 42 3D7 (FMP-1) E. coli expressed/AS02A or AS01B WRAIR Inactive
10 MSP-1 42 3D7 E. coli expressed/Alhydrogel NIH (MVDB) Inactive
11 MSP-1 42 FVO E. coli expressed/Alhydrogel NIH (MVDB) Inactive
12 AMA-1 E.coli expressed QIMR, WHO, IVR, TDR Inactive
13 GLURP long synthetic peptide EMVI, SSI Inactive
14 Combination B: RESA, MSP-1 MSP-2 STI Inactive
15 MSP-3 GLURP long synthetic peptide EMVI, SSI Inactive
MULTISTAGE VACCINES
16 Recombinant FMP-1 plus RTS,S, MSP-1 3D7 +CSP WRAIR Inactive
TRANSMISSION-BLOCKING VACCINES
17 Pfs25H P. pastoris expressed MVDB Outside the scope of this project
18 Pvs25 S. cerevisiae expressed NIH (MVDB) Outside the scope of this project

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ANNEXE > 02
ANNEXE
METHODOLOGY
HISTORICAL VACCINE PORTFOLIOS AND SNAPSHOT MODEL ASSUMPTIONS
Data on vaccine candidates from 1984 to end 2006 was General assumptions (vaccines and drugs)
collated through a literature search of major databases; for
All candidates follow the standard clinical development
example, NCBI Entrez-Pubmed, Cochrane review, and
plan developed by the PRPP (see Annexe 3). This plan was
ClinicalTrials.gov. Candidates were deemed to be in pre-clinical
tailored for different product types, including different
development if testing in animals was reported (primate or
indications for drugs (e.g. P. vivax drugs) and different
rodent models), or in clinical development if testing in human
types for vaccines (e.g. blood-stage, pre-erythrocytic, and
subjects had commenced. As not all clinical trials are
multi-stage vaccines)
published in the year that they are completed, reviews (from
All candidates proceed sequentially through the standard
1997 onwards) and expert interviews relating to historical
clinical development plan, with no timing overlap.
vaccine development were also assessed.
Attrition occurs at the end of each phase. This assumes
For the historical vaccine snapshots, data was collated using that a product will complete the phase it is in before a
the NCBI Entrez-Pubmed search engine with the keywords go/no go decision is made
MALARIA AND VACCINE for the years 1984-1986 for the Transition probabilities of success between projects are
1985 candidates, and 1994-1996 for 1995 candidates. To be independent of each other
included in the snapshot, the vaccine candidates had to be Patient enrolment will be spread evenly over year one of
active (either in or between trials) in the years examined. each trial and is independent of trial duration
Per patient costs per trial are spread uniformly throughout
STANDARD CLINICAL DEVELOPMENT PLANS
the length of the trial
Drugs Centralised management costs per trial are incurred at the
beginning of each trial.
The drug development process used in the modelling exercise
is kept as close to reality as possible; thus, our “standard” Specific assumptions for vaccines
clinical development plan (CDP) for drugs assumes all new
All vaccine candidates will be trialled in multiple formula-
anti-malarials will be developed as a fixed dose combination
tions (normally two or three) in “the West” before the
(FDC). This means that the development path modelled
best candidate is taken to “the field”. “The West” refers
assumes a product will move from phase I to phase II (for a
to those trials planned or conducted in malaria-naïve
single New Chemical Entity [NCE]), then back to phase I, II,
adults i.e. phase Ia and IIa trials (typically completed at
then III for a FDC. We also assume that NCEs currently in
Western institutions in Australia, Europe or the US). “The
clinical trials will be partnered with an existing artemisinin
field” refers to those trials planned or conducted in
derivative at the end of phase II while future NCEs will be
malaria-endemic countries i.e. phase Ib, IIb, and III trials.
partnered with another NCE. This CDP was verified with
The number of formulations to be trialled is based on data
experts (who had both industry and PDP drug development
obtained from interviews with vaccine developers on how
experience) in terms of phase progression, number of trials,
they plan to progress their candidates
patient numbers, trial locations, trial lengths etc. (see Annexe
Once in the field, projects will not be taken back to the
3A for CDP diagram).
clinic in the West
Special adjustments were carried out for the development All vaccines taken to phase III will be multistage multi-
plan of P. vivax drugs based on expert opinions. antigen vaccines, with the exception of RTS,S and the
Sanaria attenuated sporozoite vaccine. As noted by many
Vaccines
experts,17 combination vaccines targeting different stages
The CDP for vaccines is based on current practices employed of the parasite lifecycle are likely to confer better protec-
by the vaccine development groups as ascertained by on-site tion than any single antigen vaccine and are expected to
interviews with the major product developers, a review of be the way forward. As there is no international
development pathways followed by malaria vaccines agreement on how far individual candidates should be
developed to date, and published data.16 This “standard” developed before they are combined, and following rec-
CDP was verified by malaria vaccine experts from WRAIR, NIH ommendations provided by the Roadmap on combination
and LSHTM in terms of phase progression, number of trials, vaccines, we assume that all candidates will be proven
age groups, patient numbers, trial locations, trial lengths, etc. partially effective and therefore will have completed phase
(See Annexe 3b for CDP diagram). IIb trials prior to combination
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ANNEXE
Preclinical phase will be refilled at a steady rate of 5 projects Development Plans and other trial data collected via on-site
per year visits with product developers and through telephone inter-
All vaccine technology platforms have equal transition views. Each clinical trial recorded was grouped according to
probabilities of success by phase. There was not enough the type of product being investigated (drug, blood-stage
empirical data to apply different attrition rates by technol- vaccine, pre-erythrocytic vaccine, multi-stage vaccine) then
ogy platform, and experts interviewed had little experience sorted according to the phase of the trial (I, Ia, Ia/IIa, III, Ia, Ib,
of, or empirical evidence for, attrition rates for the various Ib/IIb, IIb, III, IV). Using this data the average length of each
technologies in development. trial by phase was determined. The collated clinical trial data
was also used to determine the number of trials per phase.
Specific assumptions for drugs
Each candidate was listed and grouped according to the type
Phase I will be refilled at a steady rate of 4 new drugs per of project (drug, blood-stage vaccine, etc.); and the number of
year trials conducted at each phase was recorded. The mean and
Once drugs currently in the clinical pipeline finish develop- mode were then calculated by phase and product type. All
ment, all new projects will be developed as combinations of candidates/formulations that had progressed to the following
two new drugs (i.e. two NCEs) rather than as combinations phase were included and last/ongoing phases were excluded.
of an NCE with an existing artemisinin derivative.
This historical information was then cross-checked with our
MODEL INPUTS own clinical development plan, expert opinions on vaccine
and drug R&D development paths and clinical development
Variables and assumptions used to model the malaria vaccine
plans collected during on-site visits.
and drug portfolio are listed in Table A2.1. Clarifications on
some inputs are detailed in the following sections. To determine the total phase duration, trials were grouped
according to the type of product. The time taken to transit
Table A2.1 Variables used for modelling the malaria drug and vaccine portfolio forward from one phase to the next was then determined based on
the start date of each phase. For instance, the transition time
VARIABLE DESCRIPTION between phase IIa and Ib was determined by using the start
dates of the phase IIa as compared to the start date of the
Phase Duration D Phase duration in months (per phase) phase Ib, and so forth. Formulations that had not progressed
Trial Length l Average length of trial in months (per phase) to the subsequent phase were excluded from this analysis, as
Number of trials N Number of trials (per phase) were projects in which phases overlapped. To complement
this data, we also referred to the clinical development plans
Number of candidates f Number of candidates at the start of the simulation period
provided by the product developers we interviewed and used
(t*=1) (per product type, per phase)
published material where available.18 Where empirical data
Phase transition probability p Candidate's probability of progressing to the next phase
was scant, expert opinion was sought.
(per product type, per phase)
Number of subjects PAT Number of subjects (per trial, per product type, per phase)
Number of candidates (per product type, per phase)
Per patient cost CP Direct cost per patient (per trial, per product type, per phase) Desk research was conducted to identify existing inventories
paid monthly throughout length of each trial of malaria vaccine and drug projects, including the WHO
Centralised management costs FC Centralised management costs per trial (per trial, per product Rainbow list, known product developer reports and web-
type, per phase) paid at the beginning of each trial based research sites. Information on current portfolios and
forward development plans for each project was gathered
* t=time in months from on-site visits and interviews with all the major malaria
drug and vaccine development groups, and then cross refer-
Phase duration, trial length, and number of trials
enced with phone interviews with malaria experts from
(per phase)
product development partnerships (PDPs), industry, and
Data relating to malaria clinical trials was collected by public groups (see Annexe 5 for list of experts interviewed).
conducting desk research on all published clinical trials, with
Using the information collected, malaria drug projects were
enrolment start and finish dates recorded. Clinical trial reg-
divided into five categories: clinical, preclinical, lead identifi-
istries (e.g. ClinicalTrials.gov) were also sourced to determine
cation, lead optimisation and drug discovery. Only candidates
actual or expected start and finish dates for past, current, and
from clinical and preclinical stages were included in the
future trials. This data was cross-referenced with Clinical

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ANNEXE
model. Malaria vaccine projects were divided into four cate- Phase transition probabilities used in our modelling exercise
gories: clinical (which are already incurring trial costs), were calculated based on opinions from more than 10
preclinical late-stage (projects that have completed GMP malaria vaccine experts supplemented by real-life attrition
manufacturing or are in the process of doing so), preclinical rates of the 50+ malaria vaccine candidates that have
early-stage (projects that have not reached GMP manufactur- reached the clinic since 1985. Probabilities used are as
ing but are in preclinical development and basic research). described in Table A2.2.
Projects at the basic research stage were excluded from Maximum and minimum vaccine attrition levels were calcu-
further analysis as it is very unlikely that they would reach the lated by collating expert estimates and real-life data, taking
clinical stages within the next five years. Also, basic research the “worst” and the “best” case number at each attrition
projects were felt to be ideas being tested rather than vaccine point. For instance, if experts assessed that 90% of pre-ery-
products being developed. throcytic vaccines would fail at phase IIa challenge, but
real-life data showed that only 60% of vaccines were termi-
Phase transition probability
nated at this stage, we used the 90% figure as representing
Drugs the worst case or maximum attrition scenario. This gave a
minimum to maximum range beyond which we think
The phase transition probabilities proposed by MMV in their
attrition is unlikely to go. This methodology was reviewed
2003 business plan19 were used for phase I and phase II NCEs;
with malaria vaccine developers at the Malaria Product Pipeline:
which are very close to standard industry NCE attrition rates2.
Planning for the Future Stakeholders Meeting organised by the
Thereafter, it is assumed that an NCE would return to phase
Health Policy Division (HPD) at the George Institute for
I and phase II to be developed as an FDC with an existing
International Health and the Global Forum for Health Research,
drug (as outlined in the CDP). In the scenario of an FDC at
which was held in London on the 19th and 20th of April, 2007.
this stage no attrition is assumed, since the chance of a new
FDC failing at phase I or phase II is very low; with the main Number of subjects (per trial, per product type,
risk of failure being cross-reactivity between the two per phase)
partnered drugs. There is no documentation as to what the
The number of subjects is determined using empirical data
attrition rates for an FDC at phase I or II might be (outside
collected from the various malaria drug and vaccine develop-
anecdotal evidence), so a conservative zero attrition estimate
ment groups interviewed for this report. We also sourced
is used to avoid underestimating the forecast number of trials.
data from Clinical Development Plans, from published clinical
As a new FDC progresses to phase III and registration, the trials, and clinical trial registries. The clinical trial data
attrition rates used are those proposed by MMV for NCEs. In collected was listed and grouped according to the type of
the additional partnering scenario, where two NCEs are product (drug, blood-stage vaccine, etc.) and type of trial
partnered in an FDC as opposed to an NCE plus an (phase Ia, phase Ib, etc.); then the number of subjects
artemisinin derivative, the MMV attrition rates for an NCE is enrolled per trial was recorded. Using this data, the average
applied at each stage of the development path. number of subjects enrolled per trial, product type and phase
was determined. For a multi-stage vaccine, where data is
For FDCs combining existing drugs (i.e. no NCE in the combi-
scant, a range of values based on the number of patients per
nation) we assumed zero attrition at phase III and registration
trial for blood-stage and pre-erythrocytic vaccines was used.
as this seems the most realistic scenario. For example, the
Pyramax and DHA piperaquine combinations are already In the absence of sufficient empirical data for malaria
marketed elsewhere to non-FDA standards; artesunate/ vaccines at phase Ib/IIb, IIb, and III, we calculated the sample
mefloquine, which is in registration phase, is an FDC of an size (N) required to meet specific clinical endpoints (time to
already used loose combination; and rectal artesunate is first infection, time to first clinical episode of P. falciparum
already on the market. malaria, severe malaria, or death [all causes]) using a range of
parameters (vaccine efficacy assumed, occurrence of the
Vaccines
endpoint in the control population, and drop-out rate). The
Although some general estimates of success probabilities at clinical endpoints and parameters used are listed in Table
each phase have been published for vaccines20, no figures can A2.3 and are based on those used in malaria vaccine trials
accurately predict R&D attrition for malaria vaccines as few completed to date. These were confirmed through consulta-
candidates have been trialled to date and no vaccine has tion with malaria vaccine product developers and experts. In
been registered. all cases, a follow-up period of 12 months is assumed.
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Table A2.2 Phase transition probabilities for malaria vaccines
Preclinical Preclinical Ia IIa Ia/IIa Ib adults - IIb Ib IIb III

Blood-Stage early late children children infants infants
Empirical No data No data 0.55 0.88

Experts 0.5 0.88 0.79 0.79 0.5
Average 0.67 0.84

Pre-erythrocytic early late children children infants infants
Empirical No data No data 0.55 0.39 0.88

Experts 0.5 0.88 0.53 0.1 0.88 0.5
Average 0.59 0.25 0.88

Multi-Stage early late children children infants infants
Figures used 0.5 0.88 0.67 0.84 0.5
Numbers in red not modelled forward as all pre-erythrocytic candidates go directly into Ia/IIa trials in our model, as opposed to first going to phase Ia
Protective efficacy (E) expressed as a % is: E = 100(1-r1/r0) group is defined as Qi = ni /N (i = 1, 2). Individuals are assumed
where the proportion of subjects surviving past T0 is S0 and to be recruited during an accrual period of R, and followed for
S1 (survival rate in the specified group at a specific time point). an additional period of time until a total of T years are reached.
T0 = 12 months, r0 = 1- S0 and r1 = 1- S1.
The sample size for a phase Ib/IIb trial (per product type, per
All calculations are done with PASS 2005 using the log-rank phase) is the same value as that calculated for a IIb trial as it
survival test with a 5% level of significance and power of 0.8. is assumed that the IIb component of the trial will drive the N
Sample size calculations are based on a standard 2-arm trial value.
(control group = n1 plus treated group = n2) with the plan to
have n1 = n2 = N/2. The proportion of total sample in each
Table A2.3. Clinical endpoints and parameters for malaria vaccine clinical trials
ENDPOINT VACCINE EFFICACY ENDPOINT IN THE DROP-OUT RATE

ASSUME (S1) CONTROL POPULATION (S0)
Time to first infection 30%-50% 40%-60% 10%-15%
Time to first clinical episode of P. falciparum malaria 30%-50% 10%-25% 10%-15%
Severe malaria 50% 1%-3% 10%-15%
Death (all causes) 10%-20% 8-12% 10%-15%


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Costs (per patient cost and centralised b) Minimum and maximum values of the interval where most
management cost) data points were located in the per patient cost distribution.
Drugs To the greatest extent possible, costs used in the model are
based on empirical costs. If empirical costs were insufficient
Drug trial costs are based on full direct clinical trial costs
or not available, we used the “most representative” per
incurred by MMV plus 12% management costs. As around
patient cost figure for similar trials; this approach was
half of all drug projects are now run by PDPs (with many
supported by cost estimates from developers. For example,
private sector projects now also looking for public partners),
phase III vaccine trial costs were extrapolated from PATH MVI
this figure is not likely to be too misleading going forward.
estimates as well as per patient costs for phase IIb infant
Cost assumptions for an FDC of two NCEs are different to malaria vaccine trials.
those of an FDC of one NCE plus artemisinin, as per the
Cost projections provided by the model were adjusted for
figures in Table 6 of the main report; with the higher cost for
inflation (using the NIH Biomedical Research and Development
the former combination reflecting the additional phase I and
Price Index21) and capital cost (estimated at 4% for philan-
II trials required for a second NCE (needed to precede phase
thropic and public funds 22).
I to III development of an FDC). These costs are also based on
actual figures. Industry’s share of clinical costs for vaccines are not factored
into our projections as the majority of projects in develop-
Vaccines
ment are public or have had no significant industry
Vaccine trial costs provided by Product Development involvement (e.g. MVDB, University of Oxford, Institut
Partnerships, malaria vaccine product developers, academic Pasteur). In the very few cases where industry in-kind contri-
and public groups were first analysed for completeness. Trials bution is substantial (mainly under a formal PDP such as PATH
whose costs had major gaps were then excluded (e.g. some MVI), we did not estimate this contribution, but note that
trial costs included immunological tests; others excluded much of the industry input is in the form of infrastructure
central management costs). Standardisation was then funding, which, in any case, is excluded from our analysis of
conducted under two main categories (field costs and cen- direct trial costs (e.g. GSK Biologicals contribution to satellite
tralised costs) that were then used as inputs in the modelling installation and data management capacity). This is because
exercise. Field costs (expressed as per patient cost multiplied capacity building of this type is normally amortised over
by the number of patients) comprise the costs incurred per multiple trials by multiple groups and therefore cannot be
subject (e.g. supplies and lab services) plus personnel and easily or sensibly factored into per trial costs for forward
administration costs at the trial site. Centralised cost modelling.
(expressed as a total figure per trial) convey the cost of
RTS,S is a special case since GSK Biologicals did make contri-
managing the trial (e.g. by the Western institution, product
butions to direct trial costs (e.g. to the RTS,S clinical team),
development group, or CRO).
which are not included in our analysis, leading to a potential
Capacity building costs and major capital costs associated underestimation of overall direct trial costs. However, our
with trials were excluded. All trial costs were adjusted for interviews with PATH MVI and GSK Biologicals suggest that
inflation based on the NIH Biomedical Research and these contributions are relatively modest compared with
Development Price Index 21 and expressed in US 2006 dollars. GSKs contributions to indirect costs (infrastructure, etc.) or
with PATH MVIs overall direct investment in clinical trials; and
After data points were adjusted and standardised, a distribu-
therefore, are not expected to significantly skew the final
tion was drawn to select the most representative per patient
vaccine trial cost estimates.
cost and centralised cost per trial per phase. Per patient cost
ranges were also drawn from this analysis using both manual
and statistical analysis, depending on the number of data
points available; although both methods delivered very
similar values. Forward modelling was then carried out using
the following values:
a) The “most representative” per patient cost and
centralised cost per trial per phase
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OUTCOMES
Table A2.4 describes the various outcomes obtained from

modelling the malaria vaccine and drug portfolio forward.
Table A2.4. Modelling outcomes
NAME VARIABLE DESCRIPTION FREQUENCY
Number of candidates NF Expected number of candidates at each phase (by type of product) Month
Number of trials NT Number of trials at each phase expected to occur during the year (by type of product) Month
Number of subjects NP Total number of subjects in trials (by type of product, by phase) Month
Candidates in and out NFI, NFO Number of candidates starting trials in the year (by type, by phase) Month, Year
Number of candidates ending trials in the year (by type, by phase)
Trials in and out NTI, NTO Number of new trials starting in the year (by type, by phase) Month, Year
Number of trials ending in the year at each phase (by type)
Subjects in and out NPI,NPO Number of subjects starting trials in the year (by phase) Month, Year
Number of subjects finishing trials in the year (by phase)
Centralised management costs FC Centralised management costs incurred in the West (paid at the beginning of each trial) Month
Per patient costs VC Per patients costs (by phase) Month, Year
Total and cumulated nominal costs TNC, CTNC Total and cumulated costs (per month discounted for opportunity costs) Month, Year
Total and cumulated real costs TRC, CTRC Total and cumulated costs per month discounted for inflation Month, Year
Total and cumulated costs TCC, CTCC Total and cumulated costs per month discounted for inflation and opportunity costs Month, Year

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MODEL ADJUSTMENTS
General (vaccines and drugs)

Projects known to be discontinued were manually termi-
nated, as were potential projects known to be on hold. For
instance, MSP-1 42 C1 E. coli was not included as it is
planned to be progressed in combination with AMA-1 C1
P. pastoris or the BSAM-1 project, and RTS,S/Ad35 was not
progressed as the project is on hold pending negotiations
between GSK Biologicals and Crucell
After applying attrition rates, numbers were rounded to
the nearest integer to get an integer number of candidates.
Specific adjustments for vaccines
Based on information gathered from interviews with
product development groups, multiple formulations
within the same project were grouped together and only
the lead formulation/s were moved forward (e.g. only one
formulation of GMZ-2 L. lactis will progress to phase IIb).
Candidates were included in the model at three different
entry points within a phase according to information
provided by product development groups
RTS,S progression was excluded from the modelling
process, then manually included thereafter using empirical
data gathered from interviews with PATH MVI, GSK
Biologicals, and WRAIR
Three different demand scenarios were modelled based
on maximum, mid-range, and minimum vaccine attrition
levels. Mid-point outcomes are always referred to in this
report with error bars denoting results under maximum
and minimum scenarios.
Specific adjustments for drugs
Cost projections include the cost of all trials, including
trials conducted in Asia, whereas enrolment numbers are
only for trials in Africa
Cost projections do not include costs for phase IV or label
extension trials, since these are currently undecided and
unquantifiable.
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ANNEXE > 03
ANNEXE
ANNEXE 3A. STANDARD CLINICAL DEVELOPMENT PLAN FOR MALARIA DRUGS
* In order to save time phase I of the combination could be started in parrallel to the phase IIb of the NCEs
ANNEXE
03
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Malaria Report facing pages 11
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11:50 AM
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ANNEXE 3B. STANDARD CLINICAL DEVELOPMENT PLAN FOR MALARIA VACCINES

ANNEXES > THE MALARIA PRODUCT PIPELINE
* Blood-stage vaccines will likely skip a phase IIa challenge and in this case, the phase Ia/IIa described above will only be a Ia.
** Sample size based on 50% efficacy, 10-25% incidence of clinical malaria in the control population and 12% drop out rate
*** Sample size based on 50% efficacy, 2% incidence of severe malaria in the control population and 12% drop out rate
PAGE
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ANNEXE > 04
SECTION
GROUPS & ORGANISATIONS INTERVIEWED
We gratefully acknowledge the tremendous support and assistance of the following organisations that have kindly provided
us with time, knowledge and insights during preparation of this report:
Agogo Clinical Trial Centre, Partnership (EDCTP) Malaria Research Protein Potential Inc, USA
Kumasi Centre for Laboratories, University of
European Malaria Vaccine Sanaria Inc, USA
Collaborative Research Ibadan, Nigeria
Initiative (EMVI)
(KCCR), Ghana sanofi aventis
Malaria Vaccine
GlaxoSmithKline (GSK)
African Malaria Network Development Branch Tropical Diseases Research
Trust (AMANET) Hospital Albert Schweitzer, (MVDB), National Institute Centre (TDRC), Zambia
Lambarene, Gabon of Allergy and Infectious
Bandim Health Project, United Nations International
Diseases (NIAID), USA
Guinea Bissau Ifakara Health Research and Children’s Emergency Fund
Development Centre, Medical Research Council (UNICEF)
Blantyre Malaria Project,
Tanzania (MRC), Gambia
Malawi University of Antwerp,
Imperial College London, UK Medicines for Malaria Belgium
Centers for Disease Control
Venture (MMV)
(CDC), USA INDEPTH/ Malaria Clinical University of Barcelona,
Trials Alliance (MCTA) Médecins Sans Frontières Spain
Centers for Disease Control
Epicentre, Mbarara (Uganda)
(CDC) Research Infectious Diseases Unit, University of California,
Station/Kenya Medical European Commission (EC) National Institute for San Francisco, USA
Research Institute (KEMRI), Medical Research (NIMR),
Kenya International Centre for Tanzania University of Edinburgh,
Genetic Engineering Scotland
Center for Vaccine Biotechnology (ICGEB), India Naval Medical Research
Development, University of Center (NMRC), USA University of Lausanne,
Maryland Institut de recherche pour le Switzerland
developpement (IRD), Dakar, Navrongo Health Research
(CVD-Maryland), USA University of Liverpool, UK
Senegal Centre, Ghana
Centre de Recherche en University of Tübingen,
Institut Pasteur, Paris, France Nijmegen Medical Centre,
Santé de Nouna (CRSN), Germany
Radboud University,
Burkina Faso IPTi Consortium, Barcelona, Netherlands University of Washington,
Centre National de Spain
Noguchi Memorial Institute Seattle, USA
Recherche et de Formation Johns Hopkins University, for Medical Research Clinical US Army Medical Research
sur le Paludisme (CNRFP), USA Trials Facility, Ghana Project-Kenya (USAMRU-K),
Burkina Faso
Karolinska Institute, Sweden Osaka University, Japan Walter Reed Project,
Centro de Investigação em Kumasi, Kenya
Saúde da Manhiça (CISM), Kintampo Health Research University of Oxford, UK
Mozambique Centre (KHRC), Ghana Walter Reed Army Institute
Paratek Pharmaceuticals Inc, for Research (WRAIR), USA
Division of Microbiology and Komfo Anokye Teaching USA
Infectious Diseases (DMID), Hospital (KATH), Ghana Wellcome Trust/KEMRI, Kilifi,
National Institutes of Health PATH Malaria Vaccine Kenya
London School of Hygiene & Initiative (MVI)
(NIH), USA Tropical Medicine (LSHTM), WHO/TDR, Switzerland
Directorate-General for UK PATH Meningitis Vaccine
Project (MVP), France WHO/IVR, Switzerland
Research, European Malaria Institute at Macha
Commission, Begium (MIAM), Zambia Pevion Biotech Ltd,
Drugs for Neglected Switzerland
Malaria Research and
Diseases Initiative (DNDi) Training Centre (MRTC), Pfizer
European and Developing Bamako, Mali
Portland State University,
Countries Clinical Trials USA

PAGE
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SECTION
ANNEXE > 05
LIST OF ADDITIONAL EXPERTS CONSULTED
EXPERT INSTITUTION
Jerald C. Sadoff Aeras Global TB Vaccine Foundation
Regina Rabinovitch Bill & Melinda Gates Foundation
Brian Greenwood London School of Hygiene & Tropical Medicine
Filip Dubovsky Medimmune Inc
Harold Margolis Paediatric Dengue Vaccine Initiative
Stanley Plotkin sanofi pasteur
Ian Gust The University of Melbourne
REFERENCES > THE MALARIA PRODUCT PIPELINE 87
PAGE
REFERENCES
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avaccineroadmap.net/pdfs/Malaria_Vaccine_TRM_Final.pdf. 10 Petrovsky N. 2006. Novel human polysaccharide adjuvants with dual
2 DiMasi J, Hansen RW & Grabowski HG. 2003. The price of innova- Th1 and Th2 potentiating activity. Vaccine 24 Suppl 2:S2-26-29.
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Economics 22:151-185 A, Pirmohamed M & Winstanley P. 2006. Beyond registration -
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88 G L O S S A RY > T H E M A L A R I A P R O D U C T P I P E L I N E
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GLOSSARY
Adenovirus vector See viral vector

Adjuvant A substance used to enhance or modify the immune-stimu-
lating properties of a vaccine
Antigen For malaria, a protein or other biomolecule from the malaria
parasite that is capable of triggering an immune response
Challenge test The controlled exposure of an immunised animal or human to
the infectious agent. (Also called artificial challenge or Phase
IIa trial)
Clinical Development Plan The plan linked to the process of taking a new product out of
(CDP) the laboratory and through the years of testing in human
subjects that are needed for registration (i.e. from IND sub-
mission through to end of phase III)
Clinical trial phases
Preclinical Preclinical stages involve in vitro (test tube or laboratory)
studies and trials in animals. Wide ranging dosages of the
compounds are introduced into animal subjects or to an in-
vitro substrate in order to obtain preliminary efficacy and
pharmacokinetic information and to assist in decisions
regarding the test compound, test item, or test article
phase I phase I trials are the first-stage of testing in humans, usually
a small group of healthy subjects in a non-endemic country.
This phase includes trials designed to assess the safety,
tolerability, pharmacokinetics and, where possible, pharma-
codynamics of a therapy
phase II phase II trials are performed on larger groups of subjects
once initial safety of the therapy has been confirmed in phase
I. They are designed to assess the activity and short-term
safety of the candidate in patients suffering from the disease
or condition for which it is intended. Sometimes divided into
phase IIa (usually in Western subjects) and phase IIb (usually
in endemic countries)
phase III phase III studies are large pivotal trials aimed at a definitive
assessment of the efficacy and safety of the new therapy, and
are conducted in endemic countries in hundreds or thousands
of patients. If results are satisfactory, the preclinical and trial
results are combined into a "regulatory submission" that is
provided for review to regulatory authorities in different
countries for marketing approval and registration of the new
product
phase IV phase IV trials involve post-launch safety surveillance and
ongoing technical support of a product and are designed to
bridge the gap between highly controlled licensure trials with
a few thousand subjects to uncontrolled use in millions of
patients
Contract Research A pharmaceutical CRO is an organisation that provides phar-
Organisation (CROs) maceutical research and development services for a
commercial fee. CROs do not have an intellectual property
stake in the product being developed
G L O S S A RY > T H E M A L A R I A P R O D U C T P I P E L I N E 89
PAGE
Fixed Dose Combination A formulation of two or more active pharmaceutical ingredi-
(FDC) ents combined at certain fixed doses into a single product.
The synergistic or additive potential of two or more drugs can
improve therapeutic efficacy or can delay the development of
resistance to the individual components of the combination.
FDCs reduce pill burden, which can improve medication com-
pliance
Good Clinical Practice An international quality standard given to clinical trials that
(GCP) are operated according to basic requirements; including, the
design, conduct, performance, monitoring, termination,
auditing, recording, analyses, and reporting. This practice
ensures that the data and reported results are credible and
accurate, and that the rights, integrity, and confidentiality of
trial subjects are protected. A GCP trial is one that is
conducted scientifically and ethically to these standards
Good Manufacturing That part of pharmaceutical quality assurance which ensures
Practice (GMP) that products are consistently produced and controlled to the
quality standards appropriate to their intended use and as
required by the marketing authorisation
International Conference The International Conference on Harmonisation of Technical
on Harmonisation (ICH) Requirements for Registration of Pharmaceuticals for Human
Use refers to an internationally agreed upon set of guidelines
specifically designed to improve the efficiency of developing
and registering new products.
Pharmaceutical regulatory agencies and industry representa-
tives in three regions (USA, Europe, and Japan) originally met
in 1990 and agreed upon scientific and technical criteria
required for product registration. These are regularly
monitored and updated so as to improve interpretation and
application of set criteria. When these standards are met, the
data produced may be used for regulatory purposes in each
region. See www.ich.org
Label extension Trials to extend a product’s registered use; including, into new
patient groups (e.g. pregnant women or HIV co-infected
patients), and new therapeutic areas (e.g. for P. vivax as well
as P. falciparum). Label extensions are formal regulatory trials
conducted at licensure-standard sites
Licensure trials In this report, a trial conducted to ICH standards for the
purpose of registering a new product
New Chemical Entity New drug molecules that are advanced into preclinical testing
(NCE)
Prime boost approaches Administration of one type of vaccine followed by, or
together with, a second type of vaccine. The intent of this
combination regimen is to induce different types of immune
responses and enhance the overall immune response
Product Development PDPs are defined as public health driven not-for-profit organ-
Partnerships (PDPs) isations that drive product development in conjunction with
industry groups
Recombinant protein A protein produced by inclusion of genetic material into a
foreign cell
90 G L O S S A RY > T H E M A L A R I A P R O D U C T P I P E L I N E
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Small to medium Small to medium enterprises are defined as those operating

enterprises (SMEs) with less than 100 employees, making them substantially
smaller than multinationals
Synthetic peptide Organic compounds generated by synthetic chemical tech-
niques, which are composed of two or more amino acids
linked together by a peptide bond. Often intended to
resemble or duplicate naturally occurring peptides (proteins)
Vaccine candidate Usually a combination of an antigen (a molecule that the
human body will react to so as to develop immunity against
future attacks) and a platform or mechanism to carry this
antigen into the body. Some types of vaccines require an
additional booster, or adjuvant, to make them sufficiently
potent. This combination of antigen, adjuvant and platform
make up the overall vaccine candidate
Vaccine types
Pre-erythrocytic Pre-erythrocytic vaccines are aimed at completely prevent-
ing establishment of infection (also called sterile immunity)
Blood-stage Blood-stage vaccines are aimed at controlling parasite
infection rates in the blood, thus preventing disease or death
Transmission-blocking Transmission-blocking vaccines do not prevent the vaccinat-
ed individual from contracting malaria but prevent them from
transmitting it
Multi-stage Multi-stage vaccines combine two or more of the previous
types
Viral vector A modified virus, no longer able to replicate, used to deliver
genetic material or other gene product into humans
AUTHORS > THE MALARIA PRODUCT PIPELINE 91
PAGE
AUTHORS
THE HEALTH POLICY DIVISION SYDNEY TEAM

The Pharmaceutical R&D Policy Project (PRPP) was founded at Dr Javier Guzman, Head - Sydney research team
the London School of Economics & Political Science in 2004. MBBS (Bachelor of Medicine, Bachelor of Surgery, Hons);
In 2006, the unit moved its headquarters to Sydney, Australia, MSc in Health Policy, Planning and Financing (LSHTM - LSE)
where it was consolidated as the Health Policy Division (HPD)
Dr Javier Guzman trained as
of The George Institute for International Health. The HPD
a medical doctor and worked
maintains a London office as part of the new International
in planning and implementa-
Development Centre in Bloomsbury; and is associated with
tion of primary health care
the London School of Hygiene and Tropical Medicine. The
projects in the Colombian
HPD has a wide range of clients, including the Wellcome
countryside for several years.
Trust, World Bank, Global Forum for Health Research and
He mainly worked in early
British Medical Association; and has provided policy input to
detection and treatment
numerous neglected disease fora, including the WHO
programmes of endemic
Commission on Intellectual Property Rights, Innovation and
infectious diseases such as
Public Health (CIPIH); the Rockefeller Health Innovation
tuberculosis and Chagas
Systems in Developing Countries Working Group; and the
disease. Javier moved to the
European Union "Priority Medicines for Europe and the
UK in 2002, where he worked as a Post Graduate Clinical
World" project.
Fellow in Paediatrics at the Royal London Hospital. In 2004,
Dr Mary Moran - Director, Health Policy Division he obtained his MSc in Health Policy, Planning and Financing
MBBS (Bachelor of Medicine, Bachelor of Surgery, Hons); from the London School of Economics and the London
Grad Dip FAT (Foreign Affairs and Trade); FRSM School of Hygiene and Tropical Medicine. In August 2004, he
joined the PRPP where he has worked mainly on the perform-
Dr Mary Moran trained as a
ance of different R&D models and pipelines. Javier moved to
medical doctor, working for
Australia in April 2006 and now heads the HPD research team
13 years in Emergency
at The George Institute, Sydney.
Medicine in Australia. A
post-graduate degree in Dr Margaret Jorgensen, Policy/Research Analyst
international relations and BMedSci (Hons); PhD (Molecular Microbiology)
politics at University of NSW
Margaret Jorgensen joined
and Monash University
the HPD research team in
(1995) led her into a diplo-
2006 after working for Eli
matic career with the
Lilly Australia as a Clinical
Australian Department of
Project Manager for trials
Foreign Affairs & Trade,
across several geographic
including a posting to London where she specialised in envi-
regions (Asia/Pacific, Europe,
ronmental issues and international trade. Mary subsequently
South America, and Canada).
worked with Médecins Sans Frontières initially as Director of
Prior to this, Margaret work-
the Access to Essential Medicines Campaign in Australia and
ed as an Infectious Disease
later as a Europe-based advocate on issues relating to access
Analyst and Consultant for
to medicines for neglected patients. In 2004, Mary founded
the US-based healthcare
the PRPP at the London School of Economics and Political
consulting firm Decision Resources. Here she provided phar-
Science, and supervised its transition to The George Institute
maceutical companies with in-depth research as to the
For International Health, where she is now Director of the HPD.
trends, emerging developments, and market potential of
drugs & vaccines within the major pharmaceutical markets
(US, Japan, UK, Germany, France, Italy, and Spain). Margaret
obtained her Bachelors degree from The University of Sydney,
where she majored in Infectious
92 AUTHORS > THE MALARIA PRODUCT PIPELINE

PAGE
Diseases. She completed her PhD at The University of New Sally Hughes – Administrative assistant
South Wales School of Microbiology and Immunology and BA Hons Print & Design, PGDip Elec Pub
received postdoctoral training at the Harvard University
Sally trained in print and
School of Public Health.
design and has worked in
Alina McDonald, Research Fellow academic journal publishing
BSc, LLB (Hons) for over 12 years. Before
moving to Sydney Sally
Alina McDonald trained in
worked for two years at the
science and law at the
Lancet as their Editorial
University of Sydney, majoring
Operations Manager. She
in international and health
joined the HPD in June 2007.
law. She joined the George
Institute for International
Health in January 2005 to
work on a series of health
policy Roundtables with the
Chinese Ministry of Health.
Alina has since contributed
to two Roundtables, held in
Beijing, including conducting background research and
preparing policy reports for the Ministry of Health. In early
2006, she had a short-term secondment to the World Health
Organisation in Geneva to work with the Framework
Convention for Tobacco Control team on the first Conference
of the Parties. Alina joined the Sydney-based HPD team as a
researcher in June 2006.
Dr Sarah Potter, CJ Martin Postdoctoral Fellow
BA; BSc (Hons); MiPH; PhD (Medicine)
Sarah Potter has been study-
ing malaria for more than
eight years. She completed
her Bachelor of Science
Honours year and PhD,
researching the neurological
processes of cerebral malaria,
at the Department of Path-
ology, University of Sydney.
In 2003 she comp-leted her
Masters degree in Inter-
national Public Health, also
at the University of Sydney. From 2004 until June 2006, Sarah
was an INSERM post-doctoral fellow at the laboratory of
Laurent Renia, Institut Cochin, Paris, researching malaria
immunopathology. Since July 2006, Sarah has been working
with the HPD as a Postdoctoral Fellow.
AUTHORS > THE MALARIA PRODUCT PIPELINE 93
PAGE
LONDON TEAM CONTRIBUTORS
Anne-Laure Ropars, Head - London research team Andrew Farlow
BSc (Mech Eng, Hons), MSc (Mech Eng, Hons); MA in MA Economics, University of Cambridge; M.Phil, Economics,
Political Economy and International Relations (Hons) University of Oxford
Anne-Laure Ropars originally Andrew Farlow is Research Fellow in Economics, Oriel
trained and worked as a College, University of Oxford, and Senior Research Fellow at
mechanical engineer. After the Saïd Business School, University of Oxford, where he
completing a masters degree directs a research program on dengue vaccines and a
in political economy and research group with a highly multidisciplinary approach to
international relations at the global health solutions. He holds a degree in Economics from
University of Chicago, she the University of Cambridge and an M.Phil. in Economics
worked for a number of from the University of Oxford. He has written influential work
years as a consultant special- on malaria, TB, HIV, dengue, recently-developed vaccines and
ising in European and neglected diseases; has provided independent advice to a
developing country health wide variety of public and private sector organisations; and is
systems and policies. Her a member of the Task Force on Economics and Product
clients have included the EU-based pharmaceutical industry, Profiles for TB vaccines.
philanthropic organisations (Rockefeller Foundation, Bill and
Simone Ghislandi
Melinda Gates Foundation), and government bodies (DFID,
MPhil in Economics
USAID). Anne-Laure’s project experience spans drug
procurement policy in Sub-Saharan Africa, market-based Simone Ghislandi is a Research Fellow and Tutor at Keble
mechanisms to reduce the price of essential drugs in Ghana, College, University of Oxford and a post-doc in the depart-
to drug reimbursement policies in European countries. She ment of Public Economics (Econpubblica) at Bocconi
joined the PRPP at its creation in 2004, and now heads the University, Milan. He is also a fellow at CESAV, the Health
London office of the HPD. Economics Centre of the Mario Negri Institute of Milan. In
2003, he obtained an MPhil in Economics at the University of
Hiwot Haile Selassie, Research Fellow
Oxford. He then worked as a research fellow in Pompeu
BSc Pharmacology (Hons), Msc in Control of Infectious
Fabra, Barcelona, before starting his DPhil in 2004 at the
Diseases (LSHTM)
same University with a thesis on pharmaceutical competition
Hiwot Haile-Selassie joined
and regulation. He has worked in pharmaceutical and health
the London Based HPD team
policy, publishing work in international refereed journals, and
as a researcher in 2006. Prior
in competition policy and industrial organisation, working for
to joining the HPD, and
a brief period for NERA Economic Consulting in London.
during and after completing
her masters’ degree at the
LSHTM, Hiwot worked as a
researcher on projects in
HIV/AIDS, malaria drug
policy, and sexual and repro-
ductive health. Her experience
includes conducting large
systematic literature reviews and providing analytical research
support for the development of national vaccination policies
as part of the multi-agency HIB vaccine Initiative (WHO-
LSHTM-CDC Atlanta-John Hopkins); providing research and
programme support for Interact Worldwide’s HIV/AIDS
programme; and monitoring and evaluating Zanzibar policy
on intermittent preventive treatment in pregnant women (IPTp).
94 R E S O U R C E I M P L I C AT I O N S > T H E G L O B A L M A L A R I A D R U G P O RT F O L I O
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Cover with spine 24/8/07 4:59 PM Page 1

THE MALARIA PRODUCT PIPELINE: PLANNING FOR THE FUTURE

THE GEORGE INSTITUTE FOR INTERNATIONAL HEALTH

HEALTH POLICY DIVISION

FOR FURTHER COPIES PLEASE CONTACT:

Published by The George Institute for International Health

The George Institute for International Health is an internationally recog-

> THE MALARIA PRODUCT

HEALTH POLICY DIVISION

BACKGROUND TO CLINICAL DEVELOPMENT 13

SECTION 1. THE CURRENT AND FUTURE MALARIA PRODUCT PORTFOLIO 15

1.1 MALARIA VACCINES 15

1.2 MALARIA DRUGS 26

SECTION 2. RESOURCE IMPLICATIONS 33

2.1 DEVELOPMENT COSTS 33

2.2 MANUFACTURING DEMAND 37

2.3 TRIAL SITE DEMAND AND SUPPLY 39

SECTION 3. MANAGING THE TRIAL SITE NETWORK 51

3.1 WHERE WE ARE TODAY 51

3.3 CHALLENGE TWO: MAXIMISING SYNERGIES BETWEEN SITES AND TRIALS 56

SECTION 4. VACCINE POLICY PRICE-TAGS 59

5.1 FUND MALARIA PRODUCT DEVELOPMENT 63

5.2 CONSOLIDATE THE CLINICAL TRIAL NETWORK 64

5.3 BUILD ON THE MALARIA VACCINE TECHNOLOGY ROADMAP 68

We particularly thank Simone Ghislandi, from the Department of Economics, University

ACT Artemisinin Combination Therapy IRB Institutional Review Board

Figure A. Impact of a range of vaccine policy scenarios on cost and enrolments

Figure B. Cumulative candidates at 2012 under a range of SECTION FIVE: RECOMMENDATIONS

well prepared: the concept of malaria drug treatment is

> 01 FUTURE MALARIA

Figure 1. Global malaria vaccine portfolio in November 2006 (n=47)

1.1.1 THE VACCINE DEVELOPMENT PATHWAY

ADULTS CHILDREN INFANTS

Candidates may be reformulated and re-trialled

Figure 5. Malaria vaccine types in development in 1995 and 2006

A shift to blood-stage candidates Increased antigen diversity

* All based on CSP # A total of 13 antigens represented ^ A total of 16 antigens represented

EC/AIDCO-sponsored consultancy EC-AIDCO sponsored consultancy group, commissioned to develop guidance

Figure 7. The global malaria vaccine portfolio from 1985 to 2006

* SME = small to medium enterprises

1.2 MALARIA DRUGS

developers which, if any, additional indications they will seek.

Figure 12. Global malaria drug portfolio in December 2006 (n=21)

XV DNDi is now pulling out of malaria drug development to focus on kinetoplastids

* Bioequivalence studies verify that

The phase I combination trial can also

XVIII See Annexe 2 on Methodology for attrition rates used

* Information, Education and Communication

As there is no agreed phase IV approach, we used the Lapdap

2.1 DEVELOPMENT COSTS 2.1.1 COST OF CLINICAL DEVELOPMENT OF

Table 5. Empirical clinical development costs for malaria vaccines

TOTAL COST (US$) NUMBER OF FIELD COST PER

1,028,224 30 15,274 458,224 570,000

1,958,673 450 2,730 1,228,673 730,000

XXI Phase Ib/IIb data was excluded due to insufficient data

Table 7. Empirical preclinical manufacturing costs of recombinant malaria vaccines candidates*

466,560 2000 294,192 9,072 77,760 85,536 5 20 1

Table 8. Manufacturing and toxicology costs for a candidate malaria drug

ACTIVITY AVERAGE COST (US$)

API = Active Pharmaceutical Ingredient; NCE = New Chemical Entity

VACCINE TRIAL ENROLMENTS 2007 2008 2009 2010 2011

ADULTS 200-230 230-310 170-270 200-280 90-140