Adrian Wildfire

	The concept of the human challenge model (HCM) originated from early societal attempts to halt the spread of acute diseases within their own communities. Small pox, for example, was endemic to Eurasia for 600 years with high mortality and morbidity rates and was considered one of the most common barriers to survival into adulthood. It was discovered that by using naturally attenuated material (

 minor) inoculated directly into susceptible or naïve populations (e.g. young children and unexposed individuals living in endemic areas) that death or severe disability, such as blindness or deafness, could drop to as low as 1%-2%, as opposed to 30% where the virus was contracted naturally.

	The Chinese are recorded as using such techniques in 900-1000AD,

 but it is likely that the practice actually spread to the West from India via Mamelukes trading in and around Egypt and the Mediterranean sometime in the 16

 century. Following the successes of Jesty and Jenner’s experiments in the UK, true vaccination utilizing cowpox (

 moved the human challenge model into a different era. Instead of challenge with an attenuated 

, a related virus was used to safely induce immunity. This provided a model for the deliberate inoculation of individuals with live virus for the purpose of healthcare. The practice of human challenge was further developed throughout the 18

 centuries although a series of unethical studies using gonorrhoea, syphilis and a number of other diseases in un-consented subjects (slaves, prostitutes and prisoners) damaged the perception of human challenge as a standard method for gathering data on disease progression and the efficacy of therapeutic interventions.

 century, interest was reviving in the potential of challenge models to offer insight into a number of acute, epidemic diseases. Viruses were an obvious target after the discovery of penicillin, which had cured most of the bacterial infections and DDT that had interrupted the malarial cycle in equatorial regions.

	On the back of this renewed scientific optimism, the UK Medical Research Council (MRC) founded a research facility at Porton Down in 1948 to investigate treatments for the common cold (the Common Cold Research Unit). The unit challenged volunteers with rhinoviruses until the 1980s when it was closed and research moved away, along with the leading scientists, into the private sector. The unit had, however, stimulated other researchers, especially in the US, to emulate the HCM and similar units were set up to challenge volunteers with live agents for malaria, cholera and gastroenteritis (norovirus).

	HCM trials are now being recognized as a route to the accelerated development of novel therapeutic agents. Although originally used in an academic setting, viral challenge studies have progressed since the 1990s to direct application in early phase clinical development studies by both big pharma and small biotechs alike. Phase Ib to Phase IIa viral challenge trials may be used to provide early performance indicators (efficacy), Proof of Concept (PoC), Mode of Action (MoA) and limited safety data and assist in the up / down selection of vaccine and drug candidates. Such relatively low-cost early phase trials provide information that may also be applied in the design of late phase field trials and ultimately inform go/no-go decisions. Viral challenge trials may also be used to provide insights into disease mechanisms, including the up-regulation/expression of host genes; the role of host receptors and viral entry mechanisms; as well as identifying new targets for novel compounds.

	Clinical trials using a live challenge agent have specific infection control requirements. Challenge trial design differs from classic clinical trials in two main aspects: a) the timing and duration of subject isolation (challenge agent dependent) and; b) the timing of interventions (therapeutic dependent). Approaches and methodologies are described in a number of papers and the FDA has also published a guidance document that outlines the principles that underpin challenge studies.

	The HCM has the advantage of measuring Proof of Efficacy (PoE) in human subjects during a defined period of infection with known timepoints for initiation and resolution and scheduled interventional and sampling events. The challenge agent utilized in such trials should be as close as possible to circulating strains so as to emulate the naturally observed pathology and symptomologies associated with wild type infections.

	Data gathered during HCM trials may be dose-defining or dose-timing specific. Therapeutics may fail if an intervention is initiated too early or too late in the course of an infection. Candidate drugs and vaccines may also fail due to adverse events, inferiority, lack of efficacy measures, or hypersensitivity concerns (anti-drug or anti-vaccine antibodies). The HCM may complement traditional early phase studies and act as a bridge to field trials by providing a cost-effective reality check and a window within which to modify candidate therapeutics prior to their application in late phase studies with greater numbers of subjects and the associated increased costs and timelines.

	For HCM studies, the selection of an appropriate challenge agent is essential if data is to be comparable between trials of drug or vaccine candidates. Challenge agents should be capable of inducing disease in healthy adults, have a known route of transmission as well as a well-defined disease progression (timing and severity of signs and symptoms). Although there is no definitive regulation governing the production of challenge agents, it is both accepted and expected that agents are manufactured according to current Good Manufacturing Process guidelines and that, following manufacture, the stock is subject to adventitious testing for purity, studies in animals regarding toxicology and a characterization or titration study in humans prior to authorization for use in a clinical trial. Before selecting a virus for use as a challenge agent, it is recommended to first discuss the approach to selection and manufacture with regulatory authorities via a Scientific and Technical Advice group in Europe or a pre-IND meeting in the US.

	Clinical Trial Authorization (Europe) and Investigational New Drug (US) approvals for use of challenge agents are dependent on the demonstration of efficacy, consistency (quality) and the absence of Serious Adverse Events or long-term sequelae.

	The quality of the challenge agent is only one consideration for the HCM. In a typical influenza challenge trial, subject characteristics are also important, including the immune state of volunteers prior to inoculation (determined during the screening process). Subjects must be naïve to the challenge agent to assure a high attack-rate. To ensure the challenge agent is contained within the Human Challenge Unit (HCU), high levels of infection control are required. Subjects should be quarantined prior to inoculation as well as during the study to not only contain challenge agents but also to reduce the chance of any unplanned transmission of pathogens that may enter the unit. Concomitant or super-infections may confound symptomology and immunity data and invalidate a trial.

	During the course of a HCS, viral titres may be measured to assess viral fitness in the presence or absence of drug (RT-PCR or TCID50). Other measures may include vAUC, seroconversion rates and resistance associated mutations in the viral genome. Subject fitness may be assessed via safety bloods, serum cytokine levels, physical examinations and via the use of a Symptom Scorecard – this would be additional to the objective reporting of adverse events by the study physician. Once volunteers are discharged from the study they may be followed up for a period of time to ensure neither the challenge agent nor the treatment has resulted in persistent physiological damage.

	Influenza challenge models were an early application of the HCM theory. Owing to the pandemic nature of the seasonal influenza outbreaks and the potential for the rapid, global spread of strains with high mortality rates, the establishment of aetiologies, estimation of the relative pathogenicity of circulating strains and the efficacy of candidate vaccines (live and inactivated) needed to be rapidly assessed by authorities. HCMs offer early PK/PD dynamics and proven correlates of protection: measurable markers relating subject fitness to viral fitness.

	The development of such correlates has been essential to the validation of the HCM; investigating concepts related to immunity and protection (blocking, neutralizing and eradication mechanisms).  As the model refines the understanding of humoral and cell-mediated responses, broad symptomologies may assume lesser importance compared to the dynamics of the infection cycle itself (entry and replication rather than down-stream effects).

	Although the HCM has been used primarily as a PoC and dose ranging tool,  it may also be used for more commercial purposes e.g. to fine-tune the primary indication for which it is intended to bring a product onto the market or using early PoC data to raise funding from investors for further development of a product.Some advantages of the HCM over traditional models are shown in Table 1.

Table 1. Advantages of HCM over traditional models.

	Efficiencies (e.g. low cost) of the HCM derive from the certainties inherent in its design. The high attack rate (low subject numbers), well-defined conditions and a uniform cohort reduce noise or complexity compared to a traditional 300+ subject EP field trial.  Within the HCM community there are efforts to further standardize procedures and it may become a requirement that guidelines currently being discussed by opinion leaders, within organizations such as the IABS, FDA and NIH, form an agreed template for future challenge trials. 

	The role of HCM in drug development is gathering momentum in certain therapeutic areas. In the field of respiratory illnesses, especially severe, acute viral disease, it has provided accelerated programs for a number of approaches. The National Institute of Allergies and Infectious Diseases (NIAID), Biomedical Advanced Research and Development Authority (BARDA) and the National Institute for Health (NIH) are showing interest in pooling knowledge with collaborative partners to further promote the HCM. The HCM is also evolving to encompass a wider range of challenge agents and it is possible that bacterial and parasitic agents will be manufactured to cGMP in the near future.

	From discussions with the Regulatory Authorities, it is evident that there is still a little distance to travel until human challenge studies are accepted as the norm rather than an exception in the development of certain therapeutics. However, the HCM may potentially contribute substantially to the Marketing Authorization Application process, including acting as pivotal studies; replacing traditional Phase III efficacy studies. This may occur where the cohort to be challenged very closely resembles the target population in a New Drug Application.

	However to achieve recognition as a late phase study, some of the issues highlighted by the authorities, including the limited size of the safety database, may need to be addressed by increasing the size and diversity of the HCM cohort, applying less stringent inclusion/exclusion criteria to better mimic natural populations, or by potentially combining HCM/ PoC trials with larger safety studies.

	In the field of drug discovery, the HCM has already played a pivotal role in discovery in academia (see: Walter Reed Army Institute of Research and dengue fever).

A wide range of organisms are currently being investigated globally in both resource-rich and resource-poor settings through simple challenge studies using only filtered, non-cGMP agents. It remains unlikely that such studies will progress to late phase through the regulated HCM route if the use of cGMP challenge agents remains a primary requirement, unless governments invest in the manufacture of cGMP organisms for more general access.

Adrian Wildfire is Project Director Infectious Diseases, and Bruno Speder is Head of Clinical Regulatory Affairs, both for SGS Life Science Services.

	1. http://whqlibdoc.who.int/smallate phaseox/9241561106_chp6.pdf

	2.http://www.fda.gov/downloads/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm090496.pdf and

	3. http://www.biopharminternational.com/node/247177?rel=canonical

	4. http://www.atsjournals.org/doi/full/10.1164/rccm.201002-0221OC#.VVXTQ1RBvIU )

	5. Walter Reed Army Institute of Research and its work with dengue -http://jid.oxfordjournals.org/content/209/suppl_2/S49.abstract )

Articles

The concept of the human challenge model (HCM) originated from early societal attempts to halt the spread of acute diseases within their own communities

Adrian Wildfire

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