Vaccine 32 (2014) 4708–4712

Contents lists available at ScienceDirect

Vaccine
journal homepage: www.elsevier.com/locate/vaccine

WHO report

Placebo use in vaccine trials: Recommendations of a

WHO expert panel
Annette Rid a,∗ , Abha Saxena b , Abdhullah H. Baqui c , Anant Bhan d , Julie Bines e ,
Marie-Charlotte Bouesseau f , Arthur Caplan g , James Colgrove h , Ames Dhai i ,
Rita Gomez-Diaz j , Shane K. Green k , Gagandeep Kang l , Rosanna Lagos m , Patricia Loh n ,
Alex John London o , Kim Mulholland p , Pieter Neels q , Punee Pitisuttithum r ,
Samba Cor Sarr s , Michael Selgelid t , Mark Sheehan u , Peter G. Smith v
a
Department of Social Science, Health & Medicine, King’s College London, Strand, London WC2R 2LS, United Kingdom
b
Knowledge, Ethics and Research, World Health Organization, Geneva, Switzerland
c
International Center for Maternal and Newborn Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
d
Ethical, Social and Cultural Program for Global Health, University of Toronto, Toronto, ON, Canada
e
Murdoch Childrens Research Institute, University of Melbourne, Parkville, VIC, Australia
f
Service Delivery and Safety, World Health Organization, Geneva, Switzerland
g
Division of Medical Ethics, NYU School of Medicine, New York, NY, United States
h
Mailman School of Public Health, Columbia University, New York, NY, United States
i
Steve Biko Centre for Bioethics, University of Witwatersrand, Johannesburg, South Africa
j
Instituto Mexicano del Seguro Social, Centro Médico Nacional Siglo XXI, Ciudad de Mexico, D.F., Mexico
k
Ethical, Social and Cultural Program for Global Health, St. Michael’s Hospital and University of Toronto, Toronto, ON, Canada
l
Christian Medical College, Vellore, Tamil Nadu, India
m
Hospital de Niños Roberto del Río, Santiago de Chile, Chile
n
Melbourne Law School, University of Melbourne, Carlton, VIC, Australia
o
Department of Philosophy, Carnegie Mellon University, Pittsburgh, PA, United States
p
London School of Hygiene and Tropical Medicine, London, United Kingdom
q
Vaccine Advice BVBA, Zoersel, Belgium
r
Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
s
Ministry of Health and Social Action 1, Dakar-Fann, Senegal
t
Centre for Human Bioethics, Monash University, Monash, VIC, Australia
u
The Ethox Centre, University of Oxford, Oxford, United Kingdom
v
Medical Research Council (MRC) Tropical Epidemiology Group, London School of Hygiene and Tropical Medicine, London, United Kingdom

a r t i c l e i n f o a b s t r a c t

Article history: Vaccines are among the most cost-effective interventions against infectious diseases. Many candidate
Received 27 March 2014 vaccines targeting neglected diseases in low- and middle-income countries are now progressing to large-
Accepted 2 April 2014 scale clinical testing. However, controversy surrounds the appropriate design of vaccine trials and, in
Available online 25 April 2014
particular, the use of unvaccinated controls (with or without placebo) when an efficacious vaccine already
exists. This paper specifies four situations in which placebo use may be acceptable, provided that the study
Keywords:
question cannot be answered in an active-controlled trial design; the risks of delaying or foregoing an
Vaccine trials
efficacious vaccine are mitigated; the risks of using a placebo control are justified by the social and public
Trial design
Ethics
health value of the research; and the research is responsive to local health needs. The four situations
Placebo controls are: (1) developing a locally affordable vaccine, (2) evaluating the local safety and efficacy of an existing
Risk vaccine, (3) testing a new vaccine when an existing vaccine is considered inappropriate for local use (e.g.
International research based on epidemiologic or demographic factors), and (4) determining the local burden of disease.
© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/3.0/).

1. Background

Infectious diseases continue to pose a tremendous burden of dis-

∗ Corresponding author. Tel.: +44 207 848 7113; fax: +44 207 848 7020. ease worldwide, especially in low- and middle-income countries
E-mail address: annette.rid@kcl.ac.uk (A. Rid). (LMICs) [1]. Vaccines exist for many common infectious diseases,

http://dx.doi.org/10.1016/j.vaccine.2014.04.022
0264-410X/© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

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 A. Rid et al. / Vaccine 32 (2014) 4708–4712 4709

and they are among the most cost-effective means of reducing this on large-scale clinical trials that test vaccines in Phases III and IV of
burden. However, for many debilitating and life-threatening infec- development (i.e. where preliminary testing of safety and immuno-
tious diseases in LMICs, vaccines either do not exist, or they are genicity, and sometimes efficacy, has been completed in Phase I and
insufficiently efficacious1 or unavailable to most of the population II trials). The panel, consisting of 20 experts from 11 countries, met
due to high cost. to discuss relevant issues and develop recommendations in con-
Many vaccines targeting diseases prevalent in LMICs are cur- sultation with key stakeholders in international vaccine research
rently under development. As investigators and sponsors plan (Appendix). The present paper develops the discussion and con-
large-scale clinical trials to test the safety and efficacy of these new clusions from that meeting [13].
vaccines, important ethical issues can arise in trial design, particu-
larly around the use of a placebo control arm when an efficacious 3. General ethical considerations
vaccine already exists.
Randomised, placebo-controlled trials are widely considered Given the high burden of infectious diseases, especially in LMICs,
the gold standard for evaluating the safety and efficacy of a new vac- there is an ethical imperative to develop and test new vaccines.
cine. In these trials, participants are randomized to receive either The recommendations from the panel therefore aim to facilitate
the vaccine under investigation or a placebo (i.e. an inert substance, the conduct of vaccine research that is ethical, scientifically valid,
such as a saline injection). Randomisation and the use of placebo and designed to meet important public health needs.
interventions are designed to control for confounding effects, such While this paper focuses specifically on the use of placebo
that significant differences in disease incidence or adverse effects controls, similar considerations apply to open designs in which a
between the vaccine and control groups can likely be attributed to placebo is not used, but an unvaccinated control group is included.
the vaccine. However, randomised, placebo-controlled trial designs The following recommendations assume that other common
often raise ethical concerns when participants in the control arm requirements for ethical research are respected [4,5]. In particu-
are deprived of an existing vaccine. Furthermore, testing a new vac- lar: Investigators and sponsors consult and collaborate with local
cine against placebo is scientifically and ethically fraught when the stakeholders in all phases of the research; research participants,
hypothesis being tested is whether an experimental vaccine is more or their legal representatives, give voluntary and informed con-
efficacious than one already in use in the same or in other settings. sent to study participation; participants are free to withdraw from
Currently, there is insufficient and inconsistent guidance on how research at any time, for any reason, without penalty; the research
to evaluate the use of placebo controls in vaccine trials. Most ethi- addresses an important health problem and is responsive to local
cal guidelines for research do not address vaccine trials specifically; health needs; the study design used minimizes risks and enhances
and, in those that do, the guidance regarding placebo use is limited potential clinical benefits for participants; the benefits and burdens
[2,3]. Moreover, general ethical guidelines for research – authored of the research are justly distributed; and sponsors, in consultation
by both national and international bodies – offer conflicting guid- with national or local authorities, make provisions to ensure rea-
ance on the use of placebo controls [4–11]. Some guidelines call for sonable post-trial access to interventions proven most efficacious
exclusion of placebo use altogether when there is a proven or estab- to the population from which the research participants were drawn.
lished effective intervention against the condition under study [10].
Others allow placebo use, provided the risks of withholding or 4. Ethical framework for placebo use in vaccine trials
delaying the existing intervention are either negligible or there are
compelling methodological reasons for including a placebo arm in To navigate the difficult ethical terrain of using placebo con-
the trial [4,5,7–9]. trols in vaccine trials, it is helpful to identify the conditions under
Yet, the level of risk deemed acceptable when there are com- which placebo use is clearly acceptable and clearly unacceptable.
pelling reasons for placebo use varies greatly. Most guidelines The following considerations assume that placebo interventions
allow no more than minimal risks, excluding risks of serious or (e.g. subcutaneous injections of saline solution) themselves pose
irreversible harm [4,5,9] or allowing placebo use only in the case negligible risks.
of self-limiting disease [7]. In contrast, others set no explicit risk Placebo use in vaccine trials is clearly acceptable when (a) no
limit in research that is relevant to the local population [8]. Some efficacious and safe vaccine exists and (b) the vaccine under consid-
documents openly acknowledge the “unresolved, or unresolvable, eration is intended to benefit the population in which the vaccine
conflict” around placebo use [5], a situation that has led influen- is to be tested. In this situation, a placebo-controlled trial addresses
tial regulators to disregard ethical guidance that they deem overly the locally relevant question regarding the extent to which the new
restrictive [12]. vaccine is better than nothing, and participants in the placebo arm
The lack of consistent guidance on the use of placebo controls of the trial are not deprived of the clinical benefits of an existing
raises significant ethical concern. On the one hand, investigators efficacious vaccine.
and sponsors may avoid conducting placebo-controlled trials when Placebo use in vaccine trials is clearly unacceptable when (a) a
an efficacious vaccine exists, even if such trials are scientifically highly efficacious and safe vaccine exists and is currently accessi-
necessary and potentially justifiable. On the other hand, a lack of ble in the public health system of the country in which the trial is
clear guidance may result in the conduct of placebo-controlled tri- planned and (b) the risks to participants of delaying or foregoing
als that are ultimately unethical. the available vaccine cannot be adequately minimized or mitigated
(e.g. by providing counselling and education on behavioural dis-
2. WHO expert consultation ease prevention strategies, or ensuring adequate treatment for the
condition under study to prevent serious harm). In this situation, a
Against this backdrop, the WHO Department of Ethics and Social placebo-controlled trial would not address a question that is rele-
Determinants convened an expert consultation to provide recom- vant in the local context, namely how the new vaccine compares to
mendations on the use of placebo controls in vaccine trials in the one that is currently in use, and participants would be exposed
cases where an efficacious vaccine already exists. The focus was to unacceptable levels of risk from delaying or foregoing a safe
and effective vaccine that is accessible through the public health
system.
1
We use the term “efficacious” to indicate a vaccine that reduces the incidence Between these two poles, the use of placebo controls in vac-
of the target disease. This includes vaccines that may have high or low efficacy. cine trials may be justified even when an efficacious vaccine exists,

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4710 A. Rid et al. / Vaccine 32 (2014) 4708–4712

provided the risk-benefit profile of the trial is acceptable. This Example. A conjugate vaccine against pneumococcal disease,
applies to situations where the existing vaccine is available through based on seven serotypes, had been developed and was included
the local public health system, as well as to situations where the in the routine vaccination programme of many high-income
existing vaccine is not available locally, or it is only available on the countries. Although the vaccine was expected to protect against
private market. Specifically, the risk-benefit profile of a placebo- pneumococcal disease in Africa, it was unclear if the seven included
controlled vaccine trial may be acceptable when (1) the study serotypes were appropriate for use on this continent. In addi-
question cannot be answered with an active-controlled trial design; tion, there was uncertainty about the burden of disease in Africa,
and (2) the risks of delaying or foregoing an existing efficacious vac- particularly pneumococcal pneumonia, where a causative agent
cine are adequately minimized or mitigated; and (3) the use of a cannot be isolated in most cases of pneumonia. Two additional
placebo control is justified by the potential public health or social serotypes were added to the existing seven-valent vaccine and the
value of the research; and (4) the research is responsive to local new vaccine was tested in a placebo-controlled trial in The Gambia,
health needs. Importantly, and contrary to many of the existing evaluating the impact of the vaccine against radiologically-proven
ethical guidelines on placebo use [4,5,7,9], the acceptable risks of pneumonia [16]. The trial showed 37% protection against radiolog-
withholding or delaying administration of an existing vaccine in the ical pneumonia, a finding that has been important in promoting the
placebo arm of vaccine trials may be greater than minimal when use of pneumococcal vaccines in many LMICs.
the above conditions are met.
5.3. Testing a new vaccine when an existing vaccine is considered
5. Possible situations of acceptable placebo use inappropriate for local use

The following four scenarios specify situations between the two A new vaccine is tested against a placebo because scientific
poles of clearly acceptable and clearly unacceptable placebo use experts or health officials in the trial country have determined that
in vaccine trials. In these situations, the use of a placebo control the existing vaccine should not be used in the national vaccination
may be acceptable when an efficacious vaccine exists, provided the programme because it is not considered to be sufficiently effica-
above four conditions are met. cious due to local epidemiologic, demographic, environmental, or
logistical factors. For example, the existing vaccine may provide
5.1. Developing a locally affordable vaccine
inadequate levels of protection, the protection may not be durable,
or it may require multiple vaccinations whose timely administra-
A new, low-cost vaccine is tested against a placebo because the
tion cannot be ensured under local circumstances. In this situation,
existing vaccine – although known to be, or likely to be, efficacious
a placebo arm is scientifically necessary in order to obtain suffi-
in the trial country – is inaccessible in that country’s public health
cient information on the new vaccine’s efficacy or effectiveness.
system. Accessibility may be hindered by limitations in a health
An existing vaccine may also be considered inappropriate for local
system’s ability to provide adequate support in areas including
use when it is unacceptable to a population, including the potential
administration, financing, production, distribution and infrastruc-
study participants in the trial country, based on deeply held cultural
ture. Furthermore, there should be strong reasons to believe that
or religious values (e.g. some religions do not approve of the use of
the existing vaccine is likely to remain inaccessible in the future,
bovine or porcine derived products except in emergency situations
and the new vaccine, if proven efficacious, will not be subject to the
[17], and several vaccines contain such products).
same limitations that have prevented use of the existing vaccine.
In this situation, a placebo arm might be justified to assess how Example. Three new candidate vaccines against leprosy were
effective the trial vaccine is compared to no vaccine. tested in a trial in India. Previous evidence indicated that the
existing BCG vaccination offered about 20–30% protection against
Example. Diarrhoeal disease due to rotavirus infections is a major
leprosy locally. However, Indian health officials did not consider
cause of morbidity and mortality in India. Two efficacious rotavirus
this level of protection sufficiently high to justify deploying the vac-
vaccines to protect against severe rotavirus gastroenteritis exist
cine through the national immunization programme. The five-arm
[14], but their cost remains prohibitive in many LMICs and experts
leprosy vaccine trial therefore included two control arms, with one
debate the likely local efficacy of the vaccines in some countries.
arm receiving the BCG vaccine and one receiving a placebo. The trial
Although the existing vaccines were licensed in India, they were
confirmed the low efficacy of the BCG vaccine and demonstrated
not – nor were they planned to be – introduced into the national
a ∼65% protection for two of the three new vaccines [18]. For rea-
immunization programme for reasons of cost and a lack of data
sons that are unclear, neither of the two efficacious vaccines was
on vaccine efficacy in Indian children. An Indian vaccine company
subsequently included in Indian public health programmes.
and a consortium of partner organizations conducted a placebo-
controlled trial of a new low-cost vaccine that was based on a
5.4. Determining the local burden of disease
strain of rotavirus isolated in India and targeted at infants in India
and other LMICs [15]. To mitigate risk in the placebo arm, the trial
An existing vaccine is tested against a placebo because the public
design included close monitoring of all participants to identify and
health significance of the vaccine’s introduction in the trial country
treat cases of gastroenteritis as early as possible. This system of
– that is, the vaccine’s effect on the burden of morbidity and mor-
active surveillance and early evaluation and treatment significantly
tality due to the condition(s) against which the vaccine protects –
reduced the mortality risk of severe rotavirus gastroenteritis in the
is unknown or uncertain. Comparison with a placebo yields infor-
study population.
mation on the expected public health impact of introducing the
existing vaccine, thereby facilitating informed decisions by public
5.2. Evaluating the local safety and efficacy of an existing vaccine
health officials.
An existing vaccine is tested against a placebo to evaluate its Example. Most studies had found low rates of Haemophilus
safety and efficacy in the trial country prior to uptake and intro- influenzae type b (Hib) disease in Asia, and few Asian countries
duction into the health system. As there is sometimes insufficient therefore included Hib vaccine into their routine immunization
information about the safety and efficacy of existing vaccines in programmes. Yet it was unclear whether Hib disease truly is rare, or
different settings, the status of an existing vaccine as “established whether many cases simply remain undetected. A so-called “vac-
effective” in a particular local context may need to be determined. cine probe study” was conducted in Indonesia to estimate the

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 A. Rid et al. / Vaccine 32 (2014) 4708–4712 4711

local burden of preventable Hib pneumonia and meningitis by make complex normative and empirical judgments. All of these
randomizing children in ∼800 hamlets to receive either normal stakeholders therefore have an obligation to ensure that decisions
vaccinations or normal vaccinations and the existing Hib vaccine about vaccine trial design, and especially the use of placebo con-
[19]. Hib vaccine did not prevent the great majority of pneumonia trols when an efficacious vaccine exists, are made based on the best
cases and the results did not support a major role for Hib vaccine available evidence and under consideration of all relevant reasons.
in overall pneumonia-prevention programmes. However, the study
identified high incidences of Hib meningitis and pneumonia which 7.1. Research ethics review
was used to support the inclusion of Hib vaccine in routine infant
immunization programmes in many Asian countries. All vaccine trials should undergo REC review prior to enrolling
participants. Investigators and sponsors are responsible for submit-
6. Weighing alternative trial designs ting a research protocol that gives a clear ethical justification for
the proposed trial design in line with the above considerations and
When evaluating the acceptability of using a placebo control presents relevant empirical evidence in a balanced and comprehen-
in vaccine trials, it is essential for investigators, sponsors, research sible way. The protocol should explain clearly both the scientific
ethics committees (RECs), and relevant other parties to consider justification for and the social value of using a placebo-controlled
alternative trial or study designs that might minimize risks and design and discuss the relative merits of alternative trial designs.
enhance potential clinical benefits for participants. For example, The justification for not using an existing vaccine as a compara-
in situations where a vaccine is known to be efficacious but the tor should include discussion of the acceptability, availability, and
local burden of disease is uncertain, investigators and others should accessibility of the existing vaccine for the prospective trial popu-
first evaluate study designs other than a placebo-controlled trial lation. It must be clear that the study question cannot be answered
that might allow determining the burden of disease (e.g. measuring in an active-controlled trial in the target population.
the burden of gastroenteritis before and after introducing rotavirus Furthermore, the protocol should provide evidence to support
vaccines in Latin America Desai, Oliveira [20]). Furthermore, when all empirical claims. This includes relevant evidence from previ-
a placebo-controlled trial is thought to be necessary, it is important ous clinical and non-clinical studies; evidence from consultation
to consider a design that combines the investigational vaccine or with experts (e.g. to support claims about the local safety and effi-
placebo with a routine vaccination and thus avoids giving partic- cacy of an existing vaccine); evidence from consultation with local
ipants an additional injection (e.g. pneumococcus vaccine trial in stakeholders (e.g. to show that the study infrastructure is appro-
the Gambia where the experimental vaccine or placebo was mixed priate); and evidence from formative surveys or interviews (e.g.
with the DTP–Hib vaccine [16]). to demonstrate local acceptability of the vaccine if found effec-
Investigators and others should also consider enhancing the tive). Furthermore, when an existing vaccine is not used in the trial
potential scientific and social value of vaccine trials by including country because of financial, logistical, social, religious or cultural
additional study arms. For example, when the benefits of an existing barriers to access, the protocol should provide evidence that these
vaccine are uncertain in the local population, testing a new vaccine barriers are unlikely to be overcome in the foreseeable future, and
against both a placebo and the existing vaccine would adequately that the same barriers would not obstruct use of the experimental
answer the study question, while also providing evidence to eval- vaccine should it prove efficacious.
uate the existing vaccine under local circumstances (e.g. leprosy RECs are responsible for evaluating research protocols and care-
vaccine trial in India [18]). However, trials that include an existing fully scrutinizing ethical arguments, as well as the evidence to
vaccine as a comparator typically require larger sample sizes and support empirical claims. RECs should therefore either have mem-
hence are more resource intensive than trials using a placebo con- bers who are knowledgeable about vaccine research and vaccine
trol alone. The expense, time and trial infrastructure requirements policy, or they should be open to consulting with independent
entailed by active comparator trials may discourage investigators experts in this area. Where necessary, sponsors should support
or sponsors from conducting them, thereby delaying the delivery expansion of RECs’ capacity. For instance, independent experts may
of new vaccines in populations that may need them most urgently. present available data to RECs to guide them when evaluating the
Finally, as part of the discussions around trial design, investiga- adequacy of any local evidence. Importantly, experts can be avail-
tors, sponsors and RECs should consider different types of “placebo” able for advice and discussion without participating in the REC’s
interventions. Rather than using a true placebo control (i.e. an inert actual decision-making process. In some cases, an internationally
substance), it may be appropriate to use a vaccine against a disease coordinated “pre-review” of the study protocol could support local
that is not the focus of the trial (e.g. an ongoing malaria vaccine RECs by mapping the relevant ethical issues posed by the study.
trial provides non-malaria vaccines to participants in the control This could be particularly helpful when trials are conducted in
arm [21,22]). The motivation for using these types of “placebos” countries where the local ethics review system remains remains
is to benefit participants in the control arm and avoid giving an underdeveloped. Finally, to help protect and promote trust and con-
injection with an inert substance. However, this motivation unde- fidence in research oversight, RECs should record their justification
scores the importance of ensuring that the comparator vaccine(s) for approving a placebo-controlled trial when an efficacious vac-
are proven to be beneficial in the study population. Furthermore, cine exists, and ideally make it publicly accessible. Study sponsors
it is important to recognize that trials using such “placebos” may could also make this justification publicly available in clinical trial
provide a less perfect control if the effects of the comparator vac- registries.
cine(s) confound the evaluation of the risk-benefit profile of the
experimental vaccine. For this reason, use of such “placebos” may 7.2. Consultation and collaboration with local stakeholders
also be less acceptable to regulators or public health authorities and
potentially delay approval or adoption of a new vaccine. Early and ongoing consultation and collaboration between
sponsors and host country stakeholders in government and civil
7. Procedural requirements society are essential. Before planning a trial, sponsors should con-
sult with relevant local stakeholders both about the barriers to use
Applying the above ethical framework requires that investiga- of any existing vaccine(s) and the necessary and sufficient condi-
tors, sponsors, local communities, RECs, drug/vaccine regulators, tions for uptake of a new vaccine. Sponsors should pay particular
public health authorities, policy-makers, and other relevant parties attention to political, social and practical issues that may affect

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4712 A. Rid et al. / Vaccine 32 (2014) 4708–4712

uptake. This may include formative surveys or interviews (e.g. to a vaccine already existed that was at least partially efficacious
assess the political and economic aspects of the local health sys- against the conditions under study.
tem). Sponsors and investigators are responsible for communicat-
ing appropriately about trial risks with all stakeholders. Risk assess- Acknowledgements
ments should be based on the available evidence and local context,
and they should include the risks of delaying or not conducting the Many thanks to John Boslego and David Wendler for comments
trial. During the planning and review of vaccine trials, sponsors and on a previous version of this manuscript.
investigators should be accessible to local stakeholders to discuss
the often complicated scientific and epidemiological questions that Appendix A. Supplementary data
are relevant to ethical decision-making. There is no single model
for how such consultation should take place, it may be ad hoc and Supplementary data associated with this article can be
trial-specific. Where necessary, appropriate structures for ethical found, in the online version, at http://dx.doi.org/10.1016/j.vaccine.
discussions should be created. Finally, health authorities should 2014.04.022.
facilitate ethical discussions among all involved parties prior to
approving a vaccine trial under their jurisdiction, and should make References
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