Dr Nikki Turner
Dr Nikki Turner

13 November 2014

By Dr Nikki Turner
Director of the Immunisation Advisory Centre at the University of Auckland

Superficially, Primum Non Nocere seems to be a simple principle. However, when applied to the ethics of placebo use in vaccine trials, it is not so straightforward. 

Vaccines are delivered in every country in the world via national vaccination programmes, mostly to large population groups of healthy children. For reasons of safety, community acceptability, and resource management it is important to know the vaccine profile as accurately as possible before widespread usage. Vaccines that have been in use for many years were less likely to have undergone large randomised trials, which are the gold standard today. This means that for some products, such as the inactivated trivalent influenza vaccines, there is little data comparing the biological agent with a placebo. For the introduction of any new vaccine the standard requirement is a randomised controlled trial, ideally using an inert placebo (usually saline) delivered to a control group.

Is it acceptable to give an inert substance to the control group in a vaccine randomised controlled trial (RCT)? Guideline 11 of The International Ethical Guidelines for Biomedical Research [1], states that it is acceptable to use a placebo with a control group if the use of a placebo would not add ‘any risk of serious or irreversible harm’.

RCTs clearly have an important role to play in establishing baseline data for a new vaccine and therefore the use of a placebo is generally seen as acceptable, recognising there are small risks, including the use of unnecessary injections, pain/distress, and family inconvenience. In the case of a new vaccine with the potential to reduce significant morbidity and mortality and with no existing effective intervention, the small risk is generally acceptable, so long as harm is minimised with appropriate informed consent and quality control measures in place in a well-run clinical trial. Many trials also incorporate other aspects of prevention for the control group, such as education and promotion, as seen in HIV vaccine trials [2]. Other trial designs include the use of an alternative vaccine that provides protection against an unrelated infection in the control group, or add-on vaccine approaches which offer some gain to the control arm participants. This has to be weighed up against the risk of a different vaccine in the control group creating immunological action that may bias the outcome.

However, the international world of vaccine availability is currently very inequitable: excellent new vaccines such as conjugate pneumococcal and rotavirus vaccines are well used in wealthier countries but much less so in more resource-poor countries who carry a much greater burden of the disease in their populations. The major barrier to vaccine introduction is funding and the high costs of the more recently licensed vaccines. Newer vaccines are continually being developed that are cheaper, therefore offering options to countries unable to purchase existing vaccines. Should an existing vaccine be used as a comparator every time a country or area wishes to trial a different vaccine that may be a more viable option? This may be the gold standard approach but such studies would be more resource intensive than using placebos. Because disease is likely to be prevented in both treatment groups the trial may need to be very large to be adequately powered. This approach may often delay the introduction of effective vaccines. Read the full article on pages 1 and 2 of Ethics Notes.

 

1. Council for International Organizations of Medical, S., International ethical guidelines for biomedical research involving human subjects. Bulletin of Medical Ethics, 2002 (182): p. 17.

2. rgp, H.I.V.V.S.G., Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection. Journal of Infectious Diseases, 2005. 191 (5): p. 654–665.