challenge trials in humanshttps://www.who.int/biologicals/expert_c....
Human challenge trials are trials in which participants are intentionally challenged (whether or
not they have been vaccinated) with an infectious disease organism. This challenge organism
may be close to wild-type and pathogenic, adapted and/or attenuated from wild-type with less or
no pathogenicity, or genetically modified in some manner.
In July 2014, WHO held a consultation on Clinical evaluation of vaccines: regulatory
expectations (1). One area that was considered as an important issue for facilitating vaccine
development was related to human challenge trials. It was recognized that regulation of these
trials need to be well defined by the NRAs and vaccine developers and manufacturers need to be
aware of regulatory expectations.
The document on human challenge trials should be read in conjunction with the updated
Guidelines on clinical evaluation of vaccines: regulatory expectations, adopted by the ECBS in
The scope of this document is to provide guidance to national regulatory authorities (NRAs),
manufacturers, vaccine developers, investigators, independent ethics committees, and potentially
biosafety committees and national agencies that regulate genetically modified organisms
(GMOs) if separate from the NRA. Only issues relevant specifically to the design and conduct of
clinical trials enrolling healthy adult humans capable of truly informed consent and that involve
the intentional exposure and potential infection with an infectious disease organism are
discussed. All other issues common to the design, conduct and evaluation (assessment) of
vaccine clinical trials may be found in the document Clinical evaluation of vaccines: regulatory
aspects, which is to be considered by the WHO Expert Committee on Biological Standardization
in October 2016.
Infectious human challenge studies involve deliberate exposure of human volunteers to
infectious agents. Human challenge studies have been conducted over hundreds of years and
have contributed vital scientific knowledge that has led to advances in the development of drugs
and vaccines. Nevertheless, such research can appear to be in conflict with the guiding principle
in medicine to do no harm. Well documented historical examples of human exposure studies
would be considered unethical by current standards. It is essential that challenge studies be
conducted within an ethical framework in which truly informed consent is given. When
conducted, human challenge studies should be undertaken with abundant forethought, caution,
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and oversight. The value of the information to be gained should clearly justify the risks to human
subjects. Information to be gained should clearly justify the risks to human subjects.
Although human challenge trials are not a required element of every vaccine development
programme, there are many reasons why a developer may request to conduct with humans a
challenge-protection study that might normally be conducted in animals. Animal models are
often quite imprecise in reflecting human disease, and many infectious organisms against which
a developer might wish to develop a vaccine are species-specific for humans. Human challenge
trials may be safely and ethically performed in some cases, if properly designed and conducted.
Tremendous insight into the mode of action and the potential for benefit in the relevant species
humans may be gained from challenge trials. However, there are also limitations to what
challenge trials may be able to ascertain because, like animal model challenge-protection studies,
a human challenge trial represents a model system. Because there are often such significant
limitations to animal models, the model system of the human challenge trial may significantly
advance, streamline and/or accelerate vaccine development (2).
It is important to note that not all diseases for which vaccines might be developed are suitable for
conducting human challenge trials. In many cases, human challenge with a virulent or even an
attenuated organism would not be considered ethical or safe. For example, if an organism causes
a disease with a high case fatality rate (or there is a long and uncertain latency period) and there
are no existing therapies to prevent or ameliorate disease and preclude death, then it would not
be appropriate to consider human challenge trials with such an organism. However, a human
challenge trial might be considered when the disease an organism causes has an acute onset, can
be readily and objectively detected, and existing efficacious treatments (whether curative or
palliative) can be administered at an appropriate juncture in disease development to prevent
significant morbidity (and eliminate mortality).