This text is adapted from Lambkin-Williams et al 2018, the original manuscript is open source and available here along with the citation details.
Shortening the traditional development pathway through the early use of a Proof of Concept (PoC) study that incorporates the HVC model, as shown provides essential evaluable endpoints. Unlike conventional phase 1 studies which rarely include any assessment of efficacy, almost all HVC studies include evaluable efficacy endpoints such as reduction in AUC viral load (mainly recovered from upper respiratory tract samples such as nasal wash or nasopharyngeal swab), volunteer self-reported symptoms, peak symptom score, total symptom score amongst others. Small numbers of subjects – often in the order of 30-45 per treatment group– are typically included in these rapid to execute short duration studies. The resulting safety and pharmacokinetic (PK) and pharmacodynamic (PD) data in controlled conditions, guide decisions on whether or not to progress to field studies, providing a most valuable set of data immediately after, or even as part of, the conventional phase 1 safety study.
The HVC model also opens a different development route alongside traditional phase 1 allowing rapid progress to statistically powered phase 2b studies that will generate the efficacy data needed to support licensing, while still providing suitable safety data. The FDA guidance on developing influenza therapeutics states that challenge trials cannot take the place of efficacy (phase 2) trials. The guidance states; “…Challenge trials can provide useful exposure-response and safety information, as well as an opportunity to demonstrate pharmacological antiviral activity in humans under controlled conditions outside the influenza season. Specifically, data from challenge trials can contribute to dose selection for phase 2b and phase 3 trials, and provide the opportunity to explore the effects of different times of drug initiation relative to virus exposure…”.
Challenge trial refinements are closing the gap between the experimental infection model and the natural infection setting. The HVC study duration of several weeks is shorter than a field-based phase 2 study that waits for a natural outbreak of the virus and the duration of which can be several months/years. These studies save development time when the transition between phases is fully optimised.
Importantly, unlike traditional phase 1b/phase 2 studies, HVC studies are not dependent on a natural outbreak of infection, which can occur at random, and for which the exact time of infection may not be apparent. They provide evaluable endpoints, comparative PD and PK data, along with additional biomarker data on product performance in humans. It must, however, be stated that most often such studies enrol otherwise healthy young adults which imply that the outcome of the infection in the placebo group may be seen as mild to moderate, to some extent. The safety of volunteers has to remain the priority of investigators.