Robin Rogiers

	The novel coronavirus SARS-CoV-2 is the causative agent of COVID-19 respiratory disease, a largely upper respiratory tract disease that can also descend and cause bilateral pneumonia. Its spread has outpaced those of other major infectious outbreaks in the past, and this novel coronavirus epidemic was officially declared a pandemic by the World Health Organization on March 11, 2020. 

	While a first vaccine against this coronavirus could still take some time to develop, mRNA vaccine platforms could offer an early breakthrough, although there are some concerns regarding their efficacy. For antiviral drugs the focus currently lies on repurposing of existing drugs.

	SARS-CoV-2, which thrives in cooler temperate conditions (although this does not preclude it from being prevalent in some warmer climates), is likely to move in waves from one global region to another according to seasonality. The virus shows some similarities to the SARS-CoV-1 virus and COVID-19 disease might resemble influenza disease: on average 5 days incubation, followed by fever, myalgia and a dry cough, which may progress to shortness of breath and approximately 25% of patients who are symptomatic may require hospital treatment at this point-the elderly and those with co-morbidities such as heart/lung disease being particularly susceptible. The disease can then develop into bilateral pneumonia, with patients experiencing chest pains and shortness of breath, which may require supportive therapy i.e. a ventilator.

	Some of the drugs in development for the treatment of COVID-19 disease have existed for a long time, such as nelfinavir and lopinavir, and some of the protease inhibitors from HIV research are being repurposed. Some newer drugs are also of interest: remdesivir, which has been around since the original SARS-CoV and Ebola outbreaks, is being trialed, as is chloroquine. Most potential drug treatments are still in the early phase and work is being undertaken to see how effective these will be.

	In terms of vaccines, there are about 150 in development and some of these are already in Phase 2 development. The nature of clinical advancement, and whether human challenge trials are necessary, will depend on trial sponsors and regulators, although it is expected that a challenge trial may be the only way to prove vaccine efficacy when the pandemic slows, as there will not be sufficient cases to run meaningful Phase 3 trials.

	Challenge trials or controlled human infection modelling (CHIM), brings with it a number of ethical factors which may be-or appear to be-in conflict with the usual approach to medical or clinical intervention. SARS-CoV-2 needs to be grown under a biological safety level (BSL) of 3, much like tuberculosis or cultured HIV, and is a highly infectious organism that produces serious adverse events. Although the challenge model has been an evolutionary process over 200 years since the work of Edward Jenner in 1796, the last 10 years has seen great acceleration in its use. However, it is important to carry out challenges in line with the latest regulations and to test the newest strains or challenge agents.

	Such challenge studies have become increasingly acceptable in light of the practical and ethical issues surrounding animal studies. For SARS-CoV-2 testing, animal testing can be performed using ferrets, Syrian hamster or humanoid transgenic mice, but there might not always be a good correlation with human immune responses and may have poor predictability of therapeutic effects.

	Field studies are also quite difficult in that they can be prolonged because of the slow rate of recruitment of subjects, large required sample size and they can also be complex with very diverse populations with different associated morbidities and mortalities. It may also be problematic to produce a vaccine against a virus that only appears for a few months per year. Human challenge tests (HCTs), or controlled infection models, 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 characterized and subjects are not exposed to a relatively unknown agent in the environment where many other types of co-infections occur.

	Considerations for HCTs include whether to use an attenuated strain of the virus or a homologous strain, and the different attachment pathways also need to be taken into consideration. As well as the ethical issues around using a wild-type strain of the virus, there is also the question of whether to select populations that have low risk factors and screen for the severity of disease. Additionally, the titre to be used in testing needs to be considered, as does the route of inoculation: nasal dosing may be better as oral dosing may give a higher risk of adverse pulmonary effects. These questions, along with many others will need to be discussed with regulators, with the hope that they will be able to give appropriate guidance and advice.

	Development of a SARS-CoV-2 human challenge agent

	The development of a human challenge agent has parallels with that of a drug or vaccine. The agent is first manufactured in compliance with Good Manufacturing Practice (GMP), undergoes non-clinical testing under Good Laboratory Practice (GLP) conditions and then moves into the clinical development phase, in the form a First-in-Human titration study. A human challenge agent is considered by both the EMA and the FDA to be a medicinal product and requires an IND or Clinical Trial Authorization (CTA) application before it can be used in the clinic. One major difference in its development from that of drugs or vaccines is that to date, there is no formal licensing procedure under the form of a marketing authorization application (MAA) or biologics license application (BLA) 

	For the development of a COVID-19 challenge agent, the first point to note is that there are no specific guidelines for developing challenge agents, the main reason being that the development process for a challenge agent is very specific and is highly dependent on the type of agent in question, for example, whether it is a parasite, a bacterium or a virus, all of which need to be developed in different ways.

	With SARS-CoV-2 being a BSL3 organism, this could cause logistical and strategic problems when manufacturing a human challenge agent. The manufacturing process 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 program, as the choice of challenge agent could influence the practical execution of the overall program strategy.

	As previously stated, there are no overarching guidelines for the manufacture of human challenge agents but usually vaccine manufacturing guidelines can be used as a basis for their manufacture. A combination of FDA and EMA guidelines should be looked at to ensure the development of a robust manufacturing process that complies with regulations in both the US and Europe. Based on scientific and manufacturing considerations, the challenge agent would be manufactured as a solution for intranasal delivery only and this would need to be discussed with the regulatory authorities to determine what the best approach would be, keeping the safety of the volunteers participating in the study in mind.

	A second important part of the manufacturing strategy for a COVID-19 challenge agent would be the inclusion of an adventitious agent testing program based on existing vaccine guidelines, but here a more risk-based approach could be considered. This would need to be discussed with the authorities for each case but for COVID-19 this could be based on guidance issued by both the FDA and the EMA for the development of therapeutic vaccines for COVID-19 where some of the development principles could be applicable to a human challenge agent.

	Once the agent has been manufactured and a complete testing program completed, in the EU the agent will need to be delivered by a Qualified Person (QP) before use and the manufacturing sites will require an updated GMP manufacturing license. In addition, all the Chemistry, Manufacturing and Controls (CMC) information for the agent will need to be described in the IND CMC section.

	Once any new human challenge agent moved into the manufacturing stage, non-clinical development can begin, which takes place in two parts: an 

cell-based characterization assay to show the 

infectivity properties of the agent; followed by an 

characterization study carried out in an animal model (in the case of SARS-CoV-2 this would be ferret) in compliance with GLP.

	Such a study would be negatively- and positively-controlled and the aim of both the 

studies would be to demonstrate the effectivity and infectivity of such a COVID-19 strain before moving to a FIH titration study. The starting dose for the titration would be based on the data from the animal studies, as would be the case for any other medicinal product, and the non-clinical development data would also form the basis for the design of this FIH study.

	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 Investigators Brochure (IB) and the IND application dossier. Once this has been completed, there will need to be some regulatory maintenance taking into account the fact that there are no license requirements for human challenge agents but that there is the requirement to maintain an up-to-date Investigational Medicinal Product Dossier CMC file. This should include an ongoing stability results update from a GMP stability results program 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 neutralization assay results will also need to be reported.

	Human challenge unit performance requirements

	Assuming that a BLS2 safety level is required, any human challenge unit undertaking a study into SARS-Cov-2 would need to hold a BSL2 permit and be equipped with BSL2-compliant beds, an airlock/HEPA filtered negative-pressure system and a dedicated BSL2 laboratory. All procedures would need to be discussed with the relevant regulatory authorities and are highly dependent on the nature of the challenge agent.

	Other important regulatory aspects of the study that need to be taken into consideration are the pre-screening of volunteers and the shedding of the virus in the community. 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 length of stay of volunteers in the human challenge unit needs to be confirmed based on real-life data and data from animal studies. Any subject discharge would be predicated on achieving a negative antigen test result.

	Clinical development of a SARS-CoV-2 human challenge agent

	Due to the still-limited knowledge of the number of subjects infected with COVID-19, the mortality of the infection is difficult to predict but is estimated to be about 1-2%. Symptomatology on its own is insufficient for differentiating SARS-CoV-2 from other pathogens such as influenza. Case isolation and contact tracing are essential in order to slow down the spread of infection and therefore definite diagnosis is required. The lack of a ‘gold standard’ test might lead to delayed diagnosis. The sensitivity of current PCR tests is estimated to be around 65-70% and is dependent on sampling techniques. 

	Chest CT scanning offers higher sensitivity in patients with symptomatic disease for more than 48 hours and makes it possible to diagnose patients that previously had a false negative PCR result, however radiographic signs are aspecific and make it very hard to distinguish between COVID-pneumonia and other viral pulmonary diseases such as influenza pneumonia. 

	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. During the trial, correct and sensitive markers are required to follow a subject’s health, as are adequate treatment options including the availability of intensive care units and trained staff. Next to subject safety, it is equally important to consider the safety of the clinical trial staff and, by extension, society as a whole. The 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 evaluating trial populations, whom not to include is a very important question. Age, obesity (BMI) 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. Children seem to be less affected, possibly due to receptor differences or immune imprinting from other viruses, while no increased fatality has been seen in pregnant women.

	Stopping rules for these types of trials need to be carefully formulated based on scientific and medical rationale and preferably are unambiguous and based on clinical parameters which are quick and easy to obtain such as 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. Laboratory findings and CT results can help investigators make decisions on severity and the follow-up of the evolution. There has been much speculation about the use of off-label treatment options, but it is still too early to say whether there is strong evidence for their efficacy. The fact that there is currently no rescue medication available is a significant hurdle when trying to plan a COVID-19 challenge trial. In addition, reports about medications that might harm patients are confusing the issue and no scientific consensus has been reached.

	In conclusion, as this is a droplet infection, adequate containment of the challenge agent is required. Regarding PPE, European FFP2 and FFP3 and US N95 respiratory protective masks can filter out 95% 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 nebulization. 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 blood pressure.

 is the Head of Clinical Regulatory Affairs & Consultancy, both of

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A first vaccine against this coronavirus could still take some time to develop, but mRNA vaccine platforms could offer an early breakthrough.

Robin Rogiers

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Regulatory Considerations Surrounding Human Challenge Studies with the SARS-CoV-2 Virus