Article originally written by Robin Rogiers (Prinicipal Investigator, SGS) and published in the Journal for Clinical Studies as “Advancing Towards Human Challenge Studies with the SARS-CoV-2 Virus”.
The current COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, is the current focus of numerous drug therapies and vaccine candidates. This has seen swift action from regulatory authorities to fast-track clinical programmes to find a cure or treatment; however, would it be possible that human challenge testing – or controlled infection models – could offer insights into developing therapies?
In a human challenge trial (HCT), subjects may either be inoculated with a candidate vaccine before being exposed to a live challenge virus, or dosed with an investigative therapeutic agent following experimental infection. Studies are potentially more ‘crisp’ because subjects can be infected directly, they can be cared for throughout the test period, and the tests are properly regulated and controlled. In addition, the challenge agent has been properly characterised and subjects are not exposed to a relatively unknown agent in the environment where many other types of co-infections occur.
Any step towards undertaking an HCT for SARS-CoV-2 would need to be discussed with regulators, although some of the initial considerations are discussed here.
Development of a SARS-CoV-2 Human Challenge Agent
The first choice is whether to use an attenuated or a homologous strain of the virus as the challenge agent, which must then be developed and manufactured. Although there are no specific guidelines for developing challenge agents, this process is similar to that of a drug or vaccine, and requires manufacturing in compliance with Good Manufacturing Practice (GMP), non-clinical testing under Good Laboratory Practice (GLP) conditions, and then a clinical development phase in the form of a first-in-human (FIH) titration study. A human challenge agent is considered to be a medicinal product, although there is no formal licensing procedure and steps such as a marketing authorisation application (MAA).
However, since these are medicinal products, the FDA requires an investigational new drug (IND) application to be filed for each new agent and, after GMP manufacture and non-clinical testing, a new agent needs to undergo a FIH Phase I titration/characterisation trial before being further studied and commercialised.
Presuming that a suitable agent can be manufactured safely, non-clinical development can begin, which takes place in two parts: an in-vitro cell-based characterisation assay to show the in-vitro infectivity properties of the agent; followed by an in-vivo characterisation study, carried out in an animal model (in the case of SARS-CoV-2 this would be ferret) in compliance with GLP.
There are also a number of non-clinical development human challenge agent areas that could be more condensed in comparison with traditional drug development. For example, pharmacokinetic and product metabolism studies are not usually required for human challenge agents and no formal toxicology studies are expected for this type of agent either, except if the virus is overly virulent or pathogenic, in which case the regulatory authorities may require this type of test to be carried out.
All the preclinical study results need to be described in the investigator’s brochure (IB) and the IND application dossier. This should include an ongoing stability results update from a GMP stability results programme following a classical 3-month, 6-month, 12-month reporting approach, or with an update each time the agent is used in a challenge study. Updated neutralisation assay results will also need to be reported.
Containment and Biosafety Levels
With SARS-CoV-2 being a biosafety level (BSL) 3 organism, manufacturing and actual testing needs to be carried out in suitable facilities, therefore one regulatory discussion would be whether an attenuated challenge agent could be used and considered as a BSL2 organism. This means that the GMP development strategy for the agent is linked to the scientific strategy of the whole programme, as the choice of challenge agent could influence the practical execution of the overall programme strategy.
Human Challenge Unit
Assuming that a BSL2 safety level is required, any unit undertaking a study into SARS-CoV-2 would need to hold the necessary permit and be equipped with BSL2-compliant beds, an airlock/HEPA filtered negative-pressure system and a dedicated BSL2 laboratory.
Trial Design and Safety
For a potential COVID-19 challenge trial, as with every trial, subject safety is essential and starts with the identification of the right population to enter such a trial. Volunteers would need to be pre-screened using an accredited and validated serology screening system to avoid the dangers of shedding of virus in the community, so the length of stay of volunteers in the human challenge unit needs to be based on real-life data and data from animal studies. Any subject discharge would be predicated on achieving a negative antigen test result.
During the trial, the correct and sensitive markers need to be identified to follow a subject’s health, and the availability of intensive care units and trained staff must be ensured. The safety of the clinical trial staff and the wider community’s safety is as important as the study participants, so affected subjects will need to be adequately quarantined and clinical site staff will need to have access to appropriate PPE in order to make it impossible for the virus to infect outside the quarantine area.
When recruiting subjects, evaluating the risk factors for the virus must form part of the exclusion criteria. Age, obesity and smoking are known risk factors, while common morbidities associated with bad outcomes include diabetes, cerebrovascular disease and cardiovascular diseases such as hypertension, chronic kidney disease, and COPD. Immuno-compromised subjects should not be included in a trial.
Stopping Rules and Further Actions
Stopping rules for HCTs must be carefully formulated based on scientific and medical rationale, which are preferably unambiguous, and based on clinical parameters that are quick and easy to obtain. These could be pulmonary function, oxygen saturation, temperature, spirometry, physical examination and the need for supportive care. As there are still many unknowns about the disease and its progression, it is essential to be very careful when following up on adverse events and to be very attentive in noting serious adverse reactions.
In conclusion, as this is a droplet infection, adequate containment of the challenge agent is required. The fact that there is currently no rescue medication available is a significant hurdle when trying to plan a COVID-19 challenge trial. In terms of PPE, European FFP2 and FFP3 and US N95 respiratory protective masks can filter out 95 per cent of particles when used correctly. These are the best available at present for use in high-risk procedures that create some type of aerosol, such as intubation or nebulisation. However, a large meta-analysis that has been conducted did not find any important benefit over general surgical masks in performing low-risk tasks such as transporting a patient, or obtaining a patient’s blood pressure.
We hope you enjoyed this article. If you would like further information on any of the topics discussed, don’t hesitate to get in touch.
