Milstien et al.

Malaria Journal 2010, 9:182

http://www.malariajournal.com/content/9/1/182

Open Access

CASE STUDY

WHO policy development processes for a new

vaccine: case study of malaria vaccines
Case study

Julie Milstien1, Vicky Crdenas2, James Cheyne3 and Alan Brooks*3

Abstract
Background: Recommendations from the World Health Organization (WHO) are crucial to inform developing country
decisions to use, or not, a new intervention. This article analysed the WHO policy development process to predict its
course for a malaria vaccine.
Methods: The decision-making processes for one malaria intervention and four vaccines were classified through (1)
consultations with staff and expert advisors to WHO's Global Malaria Programme (GMP) and Immunization, Vaccines
and Biologicals Department (IVB); (2) analysis of the procedures and recommendations of the major policy-making
bodies of these groups; (3) interviews with staff of partnerships working toward new vaccine availability; and (4) review
and analyses of evidence informing key policy decisions.
Case description: WHO policy formulation related to use of intermittent preventive treatment in infancy (IPTi) and the
following vaccine interventions: Haemophilus influenzae type b conjugate vaccine (Hib), pneumococcal conjugate
vaccine (PCV), rotavirus vaccine (RV), and human papillomavirus vaccine (HPV), five interventions which had relatively
recently been through systematic WHO policy development processes as currently constituted, was analysed.
Required information was categorized in three areas defined by a recent WHO publication on development of
guidelines: safety and efficacy in relevant populations, implications for costs and population health, and localization of
data to specific epidemiological situations.
Discussion and evaluation: Data needs for a malaria vaccine include safety; the demonstration of efficacy in a range
of epidemiological settings in the context of other malaria prevention interventions; and information on potential
rebound in which disease increases subsequent to the intervention. In addition, a malaria vaccine would require
attention to additional factors, such as costs and cost-effectiveness, supply and demand, impact of use on other
interventions, and distribution issues.
Conclusions: Although policy issues may be more complex for future vaccines, the lead-time between the date of
product regulatory approval and a recommendation for its use in developing countries is decreasing. This study
presents approaches to define in advance core data needs to support evidence-based decisions, to further decrease
this lead-time, accelerating the availability of a malaria vaccine. Specific policy areas for which information should be
collected are defined, including studying its use within the context of other malaria interventions.
Background
It is a priority for both the PATH Malaria Vaccine Initiative (MVI) and the World Health Organization (WHO) to
determine the most appropriate role for a future malaria
vaccine in health systems of countries at risk for malaria
mortality and morbidity. The most advanced first-generation malaria vaccine candidate has shown promising
* Correspondence: [email protected]
3

results [1-4]. If all goes well, general implementation of

RTS,S for infants six to 12 weeks of age is possible within
five years or so. The vaccine could be available for targeted use among young children five to 17 months old as
early as 2013. Other malaria vaccines are anticipated
some years later. It is imperative to define how to most
effectively develop malaria vaccine implementation policies at the national, regional, and global levels well in
advance of the first vaccine.

PATH, 13 Chemin du Levant, 01210 Ferney-Voltaire, France

Full list of author information is available at the end of the article

2010 Milstien et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.

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MVI previously developed a policy pathway for a

malaria vaccine in consultation with WHO and other
partners. One early step in MVI's policy pathway is to
identify the data--and the timing--required for a WHO
policy position on malaria vaccines. This information can
then guide MVI and its partners to develop the required
data at the correct time over the coming years.
Ultimately, this analysis can streamline the process of
establishing policy recommendations, leading to more
rapid availability of an appropriate product than has been
seen previously. The information included in this analysis
could be useful to guide other groups developing new
treatment or preventive interventions for the developing
world. Cutting time off the policy-making process will
ultimately mean that life-saving interventions can get to
those in need much sooner than has been seen historically.

Methods
Selection of interventions to study

One malaria intervention and four vaccine interventions

were analysed in detail to understand the data and their
availability to WHO policymaking bodies. The malaria
intervention was delivery of anti-malarial drugs to children during immunization sessions - intermittent preventive treatment in infancy (IPTi). The vaccine
interventions were Haemophilus influenzae type b conjugate vaccine (Hib), pneumococcal conjugate vaccine
(PCV), rotavirus vaccine (RV), and human papillomavirus vaccine (HPV). These interventions were selected as
they had relatively recently been through systematic
WHO policy development processes as currently constituted.
Study methodology

The analysis was conducted by interviewing primary contacts (see acknowledgements) and reviewing documents
and websites related to the five interventions described
above. The authors adhered to the PRISMA guidelines
for improving the quality of reporting of systematic
reviews and meta-analyses to the extent possible [5].
Because the aim of this paper is to describe and systematize the interpretation of WHO policy, the authors consulted individuals from those departments in WHO who
contributed, or were relevant to, the decisions made by
the groups in question for the five interventions analyzed.
In addition selected non-WHO staff who led initiatives
specifically supporting WHO policy development were
identified and interviewed. In total 9 individuals were
identified across the 5 interventions. The authors
reviewed websites from IVB, the IVB Strategic Advisory
Group of Experts (SAGE), GMP, Roll Back Malaria Partnership (RBM) and the IPTi Consortium. The authors
reviewed every document indicated as reference docu-

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ments for the relevant advisory groups as well as those

recommended by the interviewees, a total of over 100
documents. Of these, the majority were excluded from
the analysis as not reflecting key milestones on the policy
process. Twenty-four documents which elaborated milestones on the policy process were retained. It is not possible to know the extent of, or the role played by,
unrecognized individuals and/or undocumented decision-making.
Case description
WHO policy development process

It is likely that two expert groups will consider future policy positions for a malaria vaccine: the Global Malaria
Programme (GMP) Strategic Technical Advisory Group
(STAG) and the Immunization, Vaccines and Biologicals
Department (IVB) SAGE. The GMP Director has only
recently established the STAG, charged with developing
malaria policy recommendations, based on expert inputs
[6]. Therefore, STAG's operating processes do not yet
have the history of the corresponding group for vaccines.
STAG is advisory ultimately to the Director-General of
WHO. Three technical expert groups (TEGs), on chemotherapy of malaria, vector control, and economics and
financing, report to STAG.
Within IVB, development of vaccine policy positions
rests with SAGE [7,8]. SAGE has existed in its current
configuration since November 2005 as the principal advisory group to the WHO Director-General for development of policy recommendations related to vaccines and
immunization. It is charged with advising WHO on policies and strategies on vaccines and technologies, research
and development, delivery of immunization, and their
linkages with other health interventions for all vaccine
preventable diseases, providing strategic advice rather
than technical inputs. The deliberations of SAGE take
into consideration the recommendations of two additional WHO expert groups, the Global Advisory Committee on Vaccine Safety (GACVS) and the Expert
Committee on Biological Standardization (ECBS) [9].
WHO policy recommendations on vaccine use are
expressed in WHO vaccine position papers published in
the Weekly Epidemiologic Record. Since April 2006, these
position papers have been fully discussed and endorsed
by SAGE prior to publication; every effort is made to
coordinate their publication as soon as possible after the
relevant SAGE meeting.
SAGE may consider a matter at least three times in
deciding whether or not to issue a policy recommendation. The first meeting is to inform SAGE members of
potential new interventions on the horizon. The second
meeting, which occurs when the potential intervention is
close to the finish, is extremely important, as it provides a
clear indication of the kinds of information SAGE would

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need to make a global recommendation (i.e., a recommendation for use applicable to all target populations). If
all needed information is in place, the third meeting can
be the decision-making session, whether a utilization recommendation or a more limited position is solicited.
Since the SAGE process is dynamic and evolving, this
description may not hold in all cases.
Classification of data: WHO Guidelines

In 2003, WHO published Guidelines for WHO Guidelines

[10]. This publication emphasizes the use of systematic
reviews for evidence of effects for a policy option (such as
a treatment protocol or use of a preventive intervention)
and of evidence-based dissemination and implementation strategies [11,12]. The Guidelines outline three categories of input in development of a policy option:
Reviewing and reporting of efficacy and safety
Considering the implications of adopting the policy
positions in relation to costs and population health
"Localizing" the guidelines to their settings and
determining where the tradeoff of additional cost vs
additional benefit will be set
Because these three Guidelines categories appear relevant to the analytical processes of the advisory groups
considered, these categories have provided a framework
to define the information available and data needs for
policy decisions on the interventions considered in this
analysis (See Table 1).
Vaccine policy development

Table 1 summarizes the data available when policy positions were issued by the SAGE.
Haemophilus influenzae type b conjugate vaccine In
March 1998, WHO published the first position paper on
Hib [13]. At that time safety and efficacy data were available both in some developing countries, such as Chile, the
Gambia, and Uruguay [13], and in industrialized countries [14,15]. Efficacy was found to be at least 95 percent
against invasive Haemophilus influenzae type b disease
after three doses. There were no vaccine safety concerns.
However, there was little quantification of disease burden
outside of the industrialized world and most countries
did not have a surveillance system sufficiently tuned to
measure vaccine impact. The WHO position paper recommended the use of Hib in routine infant immunization
programmes in view of its demonstrated efficacy and
safety, but noted the lack of robust disease burden data in
Asia and in the Newly Independent States.
In 2003 and again in 2005, SAGE reviewed disease burden data in Asia [16,17], and in 2005 recommended
global implementation of Hib vaccination, unless there
were robust epidemiological evidence of low disease burden, lack of benefit, or overwhelming impediments to
implementation [17]. A new position paper on Hib was
then published in November 2006 [18]. This paper gave a
strong recommendation for Hib use, stating clearly that

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lack of local surveillance data should not delay vaccine

introduction.
Thus, in summary, a global recommendation on Hib
use was not made until 2006 for a vaccine that had been
licensed 15 years previously, in 1988, and had been covered by a WHO Position Paper since 1998. The 2006 recommendation was made almost immediately following
the presentation to SAGE of information on disease burden and efficacy in relevant target populations, and after
supply issues had been addressed. The latter element
indicated the concern of SAGE with information additional to safety and efficacy, as described in the Guidelines categories mentioned above.
Since that recommendation and other activities coincident with the establishment of the Hib Initiative, Hib
uptake has increased considerably: from 40 countries in
1998 to 103 in 2007. By the end of 2009, it is projected
that a total of 165 countries, including 61/72 of the
world's poorest countries, will have introduced the vaccine [19,20].
Pneumococcal conjugate vaccine The original WHO
PCV position paper was published in April 2003 [21].
The paper reviewed data on safety and efficacy of the
seven-valent conjugate vaccine in the United States (US)
and other industrialized countries. It noted the vaccine
was up to 97 percent effective against invasive disease
caused by the serotypes in the vaccine, with no apparent
safety concerns, that price would be an issue, and suggested that "the conjugate vaccine merits consideration
for inclusion in national childhood immunization programmes."
In November 2005 [17], SAGE noted PCV safety and
efficacy data in a wide variety of settings, including South
Africa [22], and the Gambia [23]. In addition, SAGE recognized the supply and financing issues with PCV, produced in limited quantities by a monopoly supplier, and
said, "a global recommendation made before resolution of
funding and supply issues would leave vulnerabilities that
have been experienced with the implementation of Hib."
Again, this indicates attention to issues other than safety
and efficacy.
The assembly of further data was accelerated by the
naming of a SAGE working group set up to lay the
groundwork for an evidence-based recommendation.
More information on safety and efficacy in different settings became available [24], as well as cost-effectiveness
data [25]. In November 2006, in response to this information, SAGE, satisfied with the information provided on
supply, cost, and cost-effectiveness, gave a strong recommendation for use of the seven-valent conjugate vaccine
[26]. These recommendations then formed part of the
revised position paper on PCV, published in March 2007
[27].

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Table 1: Analysis of data available for SAGE vaccine decisions according to WHO Guidelines document criteria
Intervention

Hib

PCV

RV

HPV

IPTi

Year of licensing

1988

2000

2004

2006

NA

Safety and efficacy in relevant populations

Industrialized countries only

<1998

1999

2004

2006

NA

Range of countries, missing information

1998

2003

2005

2007

2006

All data available

2006

2005

2009

2008

2009

Implications for costs and population health

Impact on disease addressed

2005

2005

2004

2007

2004

Demand, supply, financing addressed

2006

2006

2005

2008

2009

All addressing including other public health

2006

2006

--

2009

2009

Localization of data
Logistics issues addressed

NA

--

--

2007

2006

All delivery strategies addressed

2003

2003

2005

2008

2009

Successful demonstration project

2005

NA

2006

2008

2009

Date of global recommendation in WHO position paper

Nov 2006

Mar 2007

Aug 2007 (limited),

Jun 2009

Jun 2009

Oct 2009

NA = not applicable; -- = not yet completed

Thus, for PCV, licensed in 2000, and covered by a

WHO position paper since 2003, a global recommendation was made in 2007, a delay between licensure and recommendation of only seven years. This followed receipt
not only of stronger data on safety and efficacy in all target populations, but also of information on prospects for
addressing supply and financing issues.
Of the 26 countries having introduced PCV as of
August 2008, none were low or lower middle income
countries. Recently, Rwanda became the first low income
country to introduce PCV [28,29].
Rotavirus vaccine The original WHO position paper on
RV appeared in 1999 [30] and gave recommendations on
the use of the rhesus tetravalent reassortant vaccine
developed by Wyeth and licensed in the USA in 1998. At
that time there was little information demonstrating efficacy at the provided dose in developing countries, and
additional efficacy trials were begun in Africa and Asia.
When reports of intussusception appeared, WHO convened a meeting in 2000 to review the safety and efficacy
data and to provide further directions [31]. At about the
same time, the clinical trials in Africa and Asia were
stopped and the manufacturer withdrew the product.

The situation and conclusions of the meeting were captured in an updated WHO position paper published in
2003 [32], with a strong recommendation that future vaccines should be concomitantly tested in industrialized
and developing countries.
In 2004 [33], SAGE was briefed on the development of
additional RV candidates, one of which, developed by
GlaxoSmithKline Biologicals (GSK), had been licensed in
Mexico. This, and another candidate, developed by
Merck & Co (Merck), had undergone large-scale clinical
trials in Latin America, as well as in the industrialized
world, with strong evidence of safety and efficacy [34,35].
Additional trials were being initiated in Asia and Africa,
which would also investigate the question of potential RV
interference with oral polio vaccine.
Considering data assembled by the PATH Rotavirus
Vaccine Programme, SAGE in November, 2005 [17]
requested, more information from Africa and Asia where
the disease burden was very high, as well as evidence of
potential financing mechanisms. SAGE also recognized
the importance of post-marketing surveillance to assess
safety in real-life situations, and supported previous
WHO recommendations for obtaining information on

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co-administration of RV with routine childhood vaccines.

SAGE noted the need to implement strong communication strategies to prevent misconceptions regarding the
efficacy of rotavirus vaccines to prevent all childhood
diarrhoea. Approaches to this were explored by PATH
[36].
SAGE then issued a limited recommendation, captured
in a 2007 position paper [37], for use of RV in national
immunization programmes in regions where vaccine efficacy data suggested a significant public health impact,
and where appropriate infrastructure and financing
mechanisms were available. The position paper stated
that global inclusion of rotavirus vaccines into national
immunization programmes would not be recommended
"until the full potential of the current rotavirus vaccines
has been confirmed in all regions of the world, in particular in Asia and Africa."
This limited position contrasts with the global recommendation for PCV given above, because of the lack of
definitive efficacy data in some parts of the world. The
2007 RV position paper also pointed out the need for surveillance systems which would assess vaccine impact on
disease and monitor for increased incidence of intussusception [38]; expressed concern about the timing of
receipt of the first dose, which should be well before the
age of 12 weeks, after which intussusception is more
likely to occur; and advocated consideration of cost-effectiveness and affordability of the vaccine and its financial
and operational impact on the immunization delivery
system and on immunization practice.
In November, 2008, SAGE considered preliminary clinical trial results from Africa and results from cost-effectiveness studies. These results had been considered at
two expert meetings, and were provided to SAGE in
November 2008 [39]. The conclusions from these two
meetings were that there appear to be no safety concerns;
there is no evidence for interference with oral polio vaccine; and South African trial efficacy is equivalent to that
found in Latin America. SAGE considered the Asian and
African data set at its April 2009 meeting and recently
published its current position, which is a recommendation for global use [40].
In summary, for the new RVs licensed in 2004, SAGE
received data in that year demonstrating safety and efficacy in a limited number of countries. It requested more
information, including a wider range of data, and consideration of vaccine supply strategies, advocacy and logistics issues. Lacking safety and efficacy data in Asia and
Africa, the position paper contained a limited recommendation for use, only in countries where safety and
efficacy information was available, and thus a global use
recommendation was delayed.
Fourteen countries, of which eight are in Latin America, are using the vaccines as of late 2008, three countries

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have been approved for financial support, and an additional 11 are projected to apply soon [41,42]. Uniquely,
the vaccine was introduced into Latin American countries in parallel with introduction into developed countries.
Human papillomavirus vaccine The first time this vaccine was presented to SAGE was at its November 2005
meeting [17]. SAGE noted the potential communications
challenges that might exist for a vaccine against a sexually
transmitted disease, and suggested the need to study the
impact of population screening in conjunction with the
vaccine, and the financial implications of such a course.
SAGE was updated in subsequent meetings on the
global burden of cervical cancer and the available data on
safety, efficacy, and immunogenicity of the two candidate
vaccines [43]. In addition, work on cost-effectiveness and
vaccine delivery options was described, along with ongoing research on alternative schedules, delivery costs, and
acceptability. The particular areas of SAGE focus were
that the use of the vaccine was likely to bring great benefits in settings with high cervical cancer burden, especially in countries where screening programmes were
limited or non-existent; that data on long-term duration
of protection would be important in planning vaccine
delivery strategies, especially the need for a booster dose;
that the issue of delivery strategies would be critical, as
immunizing adolescents entails an expansion into a new
target group; and it noted the current high price of the
vaccine licensed in industrialized countries [44].
At its June 2007 meeting, the IVB GACVS had determined that there were no outstanding safety issues with
use of the vaccine [45]. Work to clarify the issues and to
develop candidate recommendations was performed by
an HPV Expert Advisory Group (HEAG), which was later
reconstituted as the HPV Advisory Committee (HVAC)
[46].
Candidate recommendations were presented to SAGE
in November 2008 [39], and at that time SAGE recommended that HPV be included in all national immunization programs, provided that (1) prevention of cervical
cancer and other HPV-related diseases is a public health
priority; (2) an introduction program is nationally feasible; (3) sustainable financing is available; and (4) costeffectiveness of an HPV intervention is considered. A
WHO position paper was published in April 2009 [47].
The work on HPV is an important model for the evolution of policy positions for malaria vaccines, in light of
the use of an Expert Advisory Group which included
experts in immunization, reproductive health, and cancer
to put the requisite data into a background paper and to
draft potential positions on vaccine use. A malaria vaccine policy recommendation is also likely to require participants representing a wide group of disciplines. Also,

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as noted above, key issues for the SAGE were financing

and cost-effectiveness issues as well as safety and efficacy.
In the case of HPV, there has been only a two-and-ahalf year gap between licensure and a global recommendation. Although the two HPV products are widely
licensed, the vaccine has not yet been introduced into
developing countries. This likely will happen through
GAVI processes in the poorest countries.
Policies on malaria interventions

This analysis originally considered four malaria interventions, including artemisinin-based combination therapy,
insecticide-treated nets, intermittent preventive treatment in pregnancy, and IPTi. Due to changes in the
malaria policy-making structure, the processes used and
the completeness of data available for review were not
deemed appropriate to this discussion for the first three
interventions; thus only IPTi is considered.
IPTi uses the national immunization program to distribute the anti-malarial sulphadoxine-pyrimethamine
(SP) to children during routine immunization contacts.
An analysis of the decision-making process associated
with the development of an IPTi policy is instructive in
that it has incorporated the policy development processes
of both the GMP STAG and the IVB SAGE.
Promising research results using IPTi from Tanzania
[48-50], Ghana [51], and Mozambique [52] are available,
and thus the GMP, along with the IPTi Consortium, outlined a policy development plan for this intervention [53],
which included consideration by the relevant technical
expert groups to GMP (namely, the TEG on Chemotherapy of Malaria and the STAG) and by SAGE.
Because of the SAGE policy of "horizon scanning", the
use of IPTi had already been considered in April 2006
[54]. At that time SAGE was presented with the following
information [8]: malaria disease burden in sub-Saharan
Africa; pooled data from five safety and efficacy studies in
sub-Saharan Africa; pooled data from three studies on
impact of the intervention on serology vs routine infant
vaccines; data from two cost-effectiveness studies; information on drug resistance; and one year of implementation experience.
SAGE, after reviewing data from these five trials, and
noting declining efficacy, likely related to SP resistance,
asked for more safety and efficacy data in relevant populations, including longer term follow-up to rule out
rebound (i.e. increasing disease burden later in life) and
to indicate efficacy if the putative immunization schedule
were not rigorously followed. SAGE also requested more
information on the impact of IPTi on alternative malaria
control interventions already in force, as well as the usefulness of such a strategy in areas with only seasonal
malaria transmission.
The GMP's TEG on Chemotherapy of Malaria met in
Geneva in October 2006 [55]. The group reviewed 11

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studies on IPTi conducted in Africa in areas of high

malaria endemicity. There was a consistent decline in
protective efficacy from studies of IPTi with SP over the
period 1999 to 2005. Furthermore, a review of the safety
data from unpublished studies suggested a small, not statistically significant, increase in severe dermatological
reactions (Stevens-Johnson Syndrome) in the SP arms.
The results suggesting protection from anaemia were not
supported in the further studies. No evidence was found
of rebound in malaria mortality during 5 to 12 months
after the intervention. The TEG found IPTi with SP to be
a promising intervention in settings where there is a
malaria burden for infants; where there are rigorous systems to monitor adverse events and drug resistance;
where IPTi intervention does not detract from current
efforts to scale up other malaria control strategies; where
the effectiveness of IPTi is monitored within the context
of other existing control interventions; and where the
medicines used do not compromise current and future
medicines for curative malaria treatment. The TEG
called for more research on the question of SP resistance,
optimal dosing, alternative drugs, and impact on other
malaria control strategies.
After reviewing the available data and some new studies that appeared in 2007 [56,57], WHO reconvened the
TEG in October 2007. The TEG was asked to consider
efficacy issues in the context of increasing SP resistance,
as well as to review possible dermatological reactions.
Due to safety concerns related to a few cases of rebound
of malaria susceptibility that might indicate issues if IPTi
were to be administered to healthy children in a population with declining malaria disease and increasing resistance to SP, and because of the uncertainty related to the
optimal dose and timing of administration, the TEG concluded that it could not recommend general deployment
of SP in an IPTi strategy [58]. The TEG suggested additional research in these areas and agreed to reconsider
the issue in 2008.
In 2008, a review of the evidence based on six trials was
published by the Institute of Medicine [59]. The group
recommended that there be an independent technical
review of the study data and analyses included in the
pooled analysis; that IPTi with SP first be implemented in
areas of high transmission to obtain the highest public
health impact; that public health authorities monitor evidence on changes in SP resistance; and that initial implementation be supplemented with strong efforts to
monitor safety, effectiveness, cost-effectiveness, acceptability, sustainability and logistical practicality, to help
develop guidelines for larger-scale implementation.
The TEG then considered the information in April
2009 [60], reviewing six studies with SP, and concluded
that previous safety concerns were mitigated, that the
benefits of IPTi with SP in areas where SP remained

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effective were upheld as providing 30% overall protection

against clinical malaria episodes for approximately 35
days following administration of each dose. The TEG
found there remained uncertainties on the potential
impact of IPTi with SP on incidence of severe malaria or
malaria mortality especially at low levels of malaria transmission. Recommendations were that use of IPTi with SP
should be focused on moderate to high transmission
areas where parasite resistance to SP is not high, and
where implementation would not detract from other
malaria preventive measures. Such implementation
should be accompanied by continuous surveillance
efforts.
Subsequently, SAGE reviewed these recommendations
at its October 2009 meeting [61]. SAGE was reassured
that experience with IPTi with SP administered with the
second and third doses of DTP and with measles seen in
pilot projects in Africa did not have a detrimental effect,
that EPI monitoring has been successfully adapted to IPTi
impact, and that the intervention was generally well
accepted by health workers and caregivers. SAGE therefore endorsed the use of IPTi with SP with immunization
and recommended that programs implementing this
should regularly monitor and evaluate the impact on
immunization services and performance; that impact on
serological response to pneumococcal and rotavirus vaccines should be undertaken; and that development of a
liquid SP formulation is needed.

Discussion and evaluation

Lessons learned from previous policy decisions

In the case studies considered above, issues besides safety

and efficacy in the relevant target populations have been
important and have delayed policy recommendations. In
the case of Hib, the major sources of delay were information on disease burden in specific populations and supply
issues, despite a wealth of safety and efficacy information.
Attention to disease burden and cost-effectiveness in a
variety of populations allowed a more rapid global use
recommendation to be made for PCV. For RV, the major
issue regarding a delay in a obtaining a global recommendation was the time to accumulate data on safety and efficacy in different parts of the world. However, other issues
have been addressed and RV is already introduced in a
number of countries in Latin America; countries in other
regions are poised to introduce this intervention as well.
For HPV, as well as for PCV, the use of an expert group to
develop background documents and draft candidate recommendations seems to have accelerated the process. It
has been consistently noted that the SAGE has requested
information on disease burden, cost-effectiveness, impact
on other interventions, supply, and financing issues in
addition to safety and efficacy data as part of its process
for developing policy recommendations.

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In the case of IPTi, the need for further safety and efficacy data had been the major factor in delaying a policy
recommendation for both the SAGE and the TEG. However, both groups have considered other factors, such as
impact on other interventions and disease characteristics,
and impact on EPI through pilot projects.
Data needs for malaria vaccine policy positions

Based on the above analysis for the five interventions

considered, it is expected that the SAGE will carefully
scrutinize vaccine safety data (relying on its GACVS);
require efficacy data from a range of epidemiological settings; consider implementation issues such as local disease burden data, ability of surveillance infrastructure to
measure impact, distribution strategies, and alignment of
product profile with health systems; carefully consider
the impact of an intervention on other prevention and
treatment interventions in the future (it has already done
so recently for HPV); and consider issues such as vaccine
supply, price, availability, regulatory status, and costeffectiveness. SAGE can be anticipated to have an iterative process of establishing an initial position, then modifying its recommendations over time. Its position is likely
to focus on regions where efficacy data are available,
given that malaria epidemiology varies in different parts
of the world. Its position will become more comprehensive after documentation of successful implementation in
one or more developing countries.
One particular issue that may be a focus for SAGE is the
selection of the regulatory pathway(s). If the same vaccine
could be approved for similar use for the military and
traveller markets as for the developing world, then a typical regulatory approach could be followed, with appropriate ongoing pharmacovigilance. However, if a vaccine
were developed only for use in, for example, high disease
burden areas in Africa, then a specific regulatory pathway
would have to be selected which would ensure the gathering of an adequate database on safety in that population,
oversight by a regulatory authority able to meet the
requirements for WHO prequalification, and considerations for phase 4 studies and enhanced safety surveillance in that population post approval.
SAGE will likely consider the impact of vaccines with
varying ranges of efficacy on other malaria control interventions, look at the proposed delivery schedule in the
context of national policies, and request evidence that
vaccine use will not result in displacing the disease burden to another susceptible age range. However, it is
important to point out that SAGE has been reconstituted
only recently to its current format, and thus its decisionmaking process is in evolution.
SAGE did consider the current status of the RTS,S/
AS01 candidate malaria vaccine in its October 2009
meeting [61], including the phase 2 trial data and phase 3

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trial design. Some of the issues noted above were presented as having already been considered by an "Initiative
for Vaccine Research-Global Malaria Programme Joint
Technical Expert Groups on Malaria Vaccines Entering
Pivotal Phase III Trials and Beyond."
Table 2 includes information based upon the previous
analyses, which is likely to be needed to inform policy
positions on malaria vaccines. This information could be
the target of further refinement by WHO, and in the
meantime provides indications of the data that those
working on malaria vaccines should strive to address during the development process.

Page 8 of 11

Table 2: Draft list of key data considerations information

malaria vaccine decision-making based on documentation
and WHO interviews
Safety and
efficacy in
relevant
populations

The policy-making process for a malaria vaccine

There are a number of possible models, which could be

used for malaria vaccines, based on the policy-making
experience described above. Three different models were
considered by the authors. The first, based upon the HPV
model, is a time-limited group representing TEG and a
sub-group of SAGE, which could then report back to
SAGE and STAG. The second potential model, drawing
on the RV experience, is to use or modify the membership of the existing MALVAC committee, a group advisory to IVB considering research and development
(R&D) approaches to a malaria vaccine [62]. The committee's focus on R&D may limit its capacity to provide
guidance on policy recommendations for vaccine implementation.
The third approach is modelled upon the IPTi process
using the appropriate TEG to provide SAGE and STAG
with recommendations. However, no member of the currently established TEG on Chemotherapy of Malaria has
expertise in immunology or vaccinology, and thus the
group would not be able to effectively review data on
immune response, impact on response to other vaccines,
schedule information, logistics and delivery, and supply
issues. A modification of this is to convene a new TEG
under joint WHO immunization and malaria leadership,
which would draw upon expertise from both disciplines.
This in fact has been done, as noted above, convening its
first meeting in mid-2009.

Conclusions
With the above as background, several conclusions can
be drawn:
1. Although efficacy and safety in the relevant target
population, including displacement of disease to
another susceptible age range, are crucial components of any policy development process, additional
concerns may also be important in the formulation of
policy positions. These include issues related to costs
and population health, such as supply and demand
issues, financing issues, cost-effectiveness, the impact

Safety
An acceptable safety profile
Freedom from "rebound" effect, that is, enhancing
disease incidence in target groups following use:
needs follow-up population monitoring
Positive evaluation from WHO GACVS
No significant adverse impact on other malaria
prevention and treatment strategies (i.e. increasing
adverse events from another product) or on
response to concomitantly administered vaccines
Safety evaluated in immunologically compromised
groups, e.g. HIV-infected
Efficacy
Acceptable level of reduction of disease-related
morbidity and/or mortality in target populations
Efficacy demonstrated in different malaria
endemicity settings
Delivery schedules, dosing and administration route
feasible and consistent with burden of disease in
target countries

Implications
for costs and
population
health

Supply, financing, and cost-effectiveness issues

Availability of product under the regulatory
oversight of a fully functional regulatory authority
and/or prequalification
Available supply related to anticipated demand
Affordability
Means of monitoring impact to feed into costeffectiveness assessment
Prospects for competitive vaccine market
Impact on other public health interventions
Vaccine delivery strategies to reach desired target
groups (e.g., catch-up immunization where relevant)
Impact of vaccine use on compliance with other
interventions, e.g. ITN
Community perception of given malaria vaccine
products given their likely characteristics
Impact of the vaccine demonstrated in the context
of other malaria control strategies

Localization
of data

Local applications of the intervention

Evidence sufficient for local decision making
available to the appropriate in-country groups (such
as Immunization Advisory Committee, Interagency
Coordinating Committee, etc), including, as
relevant, national stakeholders and decision makers
and key partners
Ability to deliver vaccine through local cold chains
Specific evidence for unique epidemiological
situations available, if applicable
Information from demonstration projects available
particularly where new target groups or specific
product acceptance issues are involved

Milstien et al. Malaria Journal 2010, 9:182

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of use on other interventions, and issues specific to

the local situation, such as distribution and cold chain
considerations. Specific issues unique to a malaria
vaccine listed in Table 2 will need consideration.
2. All efforts should be made to document the use of a
malaria vaccine in the context of other malaria treatment and prevention interventions, and to rigorously
document the impact.
3. In the analyses above, SAGE issued initial positions,
while asking that demonstration projects or pilot
introduction studies be done in some cases (e.g.
HPV), where a new target population or a specific
product communication issue is involved. Such studies could assist to refine the WHO policy recommendation.
4. For a product with a complex policy development
process like a malaria vaccine, a specially convened
working group may be useful to assist both GMP and
IVB policy groups.
5. A strong recommendation in a WHO position
paper is important for efficient decision-making on
use by developing countries, as seen, for example, in
the case of Hib. The vaccine interventions studied in
this analysis demonstrate a very positive shortening of
the time required by WHO to issue such recommendations.
This paper has taken the unique step of trying to identify the data and processes required at the WHO policy
level for the introduction of a new intervention. While
the focus has been on SAGE and STAG processes for
malaria vaccines, it is critical to also find the correct balance of input from national and regional levels. Organizations can work in advance to address data requirements;
however, lessons from historical precedents, as developed
in this paper, or specific inputs of WHO, are required to
guide this work. Developing data in advance and further
clarifying policy processes will allow policy-making bodies to continue their trend towards more efficient decisions, while also considering the full range of essential
information. Shaving months and years off of the policymaking process will ultimately mean that life-saving
interventions can get to those in need much sooner than
has been seen historically.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
JM performed the analysis and drafted the paper. VC participated in the analysis and contributed to the drafting of the paper. JC participated in the initial
planning for the analysis, participated in the analysis and contributed to the
drafting of the paper. AB conceived the study, contributed to the analysis and
to the drafting, and provided overall guidance and oversight. All authors have
read and approved the final manuscript.

Page 9 of 11

Acknowledgements
The authors are pleased to acknowledge useful inputs without which this
paper would not have been possible from Philippe Duclos, Vasee Moorthy,
Zarifah Reed (currently affiliated with Regional Emerging Diseases Intervention
(REDI) Centre, Singapore) and Kamini Mendis, WHO; from Jane Crawley, IPTi
Consortium and UK Medical Research Council Clinical Trials Unit; Rana Hajjeh,
the Hib Initiative, Johns Hopkins University Bloomberg School of Public Health;
Orin Levine, International Vaccine Access Center, Johns Hopkins Bloomberg
School of Public Health; Stephanie Schrag, Centers for Disease Control and Prevention; and John Wecker, PATH Rotavirus Vaccine Program. The authors are
not affiliated with WHO and this paper does not necessarily represent the
views of WHO.
This work was supported by funding from the Bill and Melinda Gates Foundation. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Author Details
of Maryland School of Medicine, 3 bis rue des Coronilles Rsidence
Parc de Clmentville Btiment C, 34070 Montpellier, France, 2PATH Malaria
Vaccine Initiative, 7500 Old Georgetown Road, #1200 Bethesda, MD 20814, USA
and 3PATH, 13 Chemin du Levant, 01210 Ferney-Voltaire, France
1University

Received: 22 March 2010 Accepted: 24 June 2010

Published: 24 June 2010

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doi: 10.1186/1475-2875-9-182
Cite this article as: Milstien et al., WHO policy development processes for a
new vaccine: case study of malaria vaccines Malaria Journal 2010, 9:182

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