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International Clinical Trials

Human Resources

Clinical trials for anti-infective agents and vaccines have traditionally been carried out via field trials in clinics and hospitals. However, a couple of decades ago the concept of the human challenge study was introduced by the Common Cold Research Project in the UK, where healthy people were infected with rhinoviruses in the search for treatments and vaccines. The challenge model involves the inoculation of subjects with a candidate vaccine before they are exposed to the virus or dosed with an investigational therapeutic agent after infection.

The concept has since been extended to other viruses, and even bacterial and parasitic infections. Indeed, while ethics preclude challenges with chronic, incurable infections – and regulators still demand full field trials for the later stages of clinical development – human challenge studies have become increasingly crucial in verifying proof-of-concept for suitable infections.

Predictive Tool

One of the drawbacks of field trials is that many infections, such as influenza and respiratory viruses, are seasonal. If the infection has only low incidence (it may be as low as 5% for influenza), it can be difficult to recruit sufficient subjects for a successful proof-of-concept study, and it could take several seasons across more than one hemisphere, which greatly adds to costs. The cohort in the field will also be less well matched in terms of lifestyle and co-infections, which can impact greatly on trial results. It is important to understand the clarity and purity of the datasets generated.

Using a human challenge study, the timing of infection can be controlled so the precise initiation point is known. This makes it easier to follow the course of the infection and understand how the intervention affects viral symptomology. It further allows for better calculation of the drug concentration in the blood, as the measurement points are pinpointed exactly. In the field, the timing of infection is known only roughly; and while this can be back-predicted up to a point by a careful study of viral loads, it is not as accurate.

A human challenge study has controlled conditions, a controlled cohort, and both initiation point and periodicity are clear. It offers advantages from a research standpoint, as it facilitates taking a series of samples to look at pharmacokinetics and pharmacodynamics of a drug treatment, alongside immunology and genetics across the course of disease progression. In addition, it gives a far better picture of the correlates of progression. Pharma and biotech companies are now looking seriously at the human challenge model as a predictive tool for expensive field studies, whose outcomes are frequently unpredictable.

Dedicated Unit

In the early days of human challenge studies, they were typically carried out in open wards; however, this reduces infection control. Although tests for many different infectious organisms are run, one person with a secondary infection is sufficient to infect the other study subjects and to confound the research.

For this reason, subjects should be isolated, and this is much easier to do within a dedicated clinical pharmacology unit or a standalone human challenge unit (HCU). These are typically located in a hospital setting, close to Accident and Emergency and Intensive Care facilities, should anything untoward happen within the trial. A further benefit is that dedicated staff at the location will be experienced in specialist interventions and techniques such as lumbar punctures, nasopharangeal washes or alveolar lavage – these are much more difficult to carry out in a basic respiratory ward and nigh-on impossible in a general medical ward.

Standalone HCUs nowadays also feature a good deal of automation, removing subjectivity and moving towards a more objective analytical viewpoint that takes away subject bias. This assists in the collection and collation of a wide range of physiological and biochemical metabolic markers, which provide an insight into whether a therapeutic is effective or not, and that adverse events are being observed. For example, if liver function is greatly increased or creatinine kinase levels rise substantially, this is likely to be a sign that something awry is happening.

Furthermore, an HCU sees patients being cared for by a large body of clinical staff with experience in a range of conditions. The substantial amount of testing that goes on may uncover underlying conditions in patients who thought they were otherwise healthy.

Ethical Questions

But, there are some drawbacks to using an HCU to carry out these trials. Recruitment can be an issue. While this is not restricted to human challenge tests and is true for many trials performed in a clinical pharmacology unit, people may be wary of being in isolation for up to two weeks.

More specifically for human challenges, there are ethical considerations. In a field trial, where patients can be ‘naturally infected’, participation and treatment in the study will lead to the subject's treatment and potential cure – or, in case of a vaccine study, to prevent the infection from occurring. There is a clear advantage for the participant. In a viral challenge study, with patients deliberately infected with a virus, there is an argument that this contradicts the principle of ‘do no harm’ enshrined in the Hippocratic Oath, as they are being made ill.

Of course, there is the counter-argument that it is being done for the greater good of the human race, especially in the case of a vaccine against an infection that could become pandemic, with the additional bonus that participants will now be immune to that organism. Similarly, if it is a current circulating strain, it is to their benefit, too: indeed, in some ways, the trial is simply a vaccination programme.

Sample Management

Human challenge studies focus the need for sampling, especially if there is a very concentrated pharmacokinetic schedule. However, this would be even more difficult to manage within a community environment. Other functions that might be beyond the capabilities of a communitybased trial range from neurological tests – such as electroencephalography, positron emission tomography and cerebrospinal fluid sampling – to metabolic studies like glucose clamping and 14C mass balance studies, as well as lipopolysaccharide (LPS) challenges to look at immunological responses.

Some of these – for instance, bronchoprovocation tests that aim to induce asthma attacks, or LPS challenges to provoke immune responses – are probably not wise to conduct in the community. In addition, when performing challenge studies on volunteers with pre-existing medical conditions, a controlled environment is crucial in order to closely monitor the safety of subjects.

Rapidity is another advantage of a standalone HCU. Sample processing and analysis, culturing and pathology tests give faster results if analysis is performed locally. Also, monitoring and blinding is simpler: if all the subjects are in one place, safety data is more easily observed and maintained, remaining in a single database. Modern telemetry systems are very helpful in removing a lot of the subjective analysis.

The clinicians and scientists within an HCU will have the experience to distinguish between viral-associated adverse events and those related to treatment – the symptoms to expect from the viral infection are known and thus, beyond that, are likely to be a result of the treatment. A runny nose might be expected; renal involvement might not.

Isolation Case Study

As an example, a Phase 2a randomised, double-blind, placebo-controlled study was carried out within a dedicated HCU to assess the safety, tolerability and antiviral activity of a single intravenous dose of an investigational monoclonal antibody in healthy subjects inoculated with the H1N1 infl uenza A virus.

A total of 60 volunteers were included in the study, in five cohorts of 12. Each cohort spent 11 days in isolation within the unit, giving an overall study duration of 56 days. Running the trial in smaller cohorts sequentially gave fast turnaround of results without exposing large numbers of individuals to a new treatment at the same time, with the attendant safety risks that creates. If adverse events were observed in the initial cohort, the dosage could be adapted, or additional support therapy included in the regimen. If the entire cohort were run in one go, a second cohort would still have to be run for comparative analysis purposes, adding significantly to the cost.

Stepwise studies like this offer the best of both worlds – they still provide relatively fast results, while reducing the opportunity for something avoidable to go wrong. An HCU gives time for contemplation, early analysis of results so anything that may confound the study down the line can be taken into account, and the opportunity to clearly defi ne the volunteer or subject population.

In the above example, the HCU was advantageous for a number of reasons. The setting facilitated the measurement of nasal mucosa pharmacokinetics, and both isolating and checking subjects for a negative serology for H1N1. Regulatory constraints that had to be met included those around working with a live challenge agent and ensuring infection control, both within the unit itself and the wider community. It also assisted in managing any exacerbations of underlying disease that might be provoked by the challenge.

Ultimately, the trial met the demands of the regulator, which approved the isolation facility, trial concept and challenge testing with no request for additional safety reporting. The Good Laboratory Practice and Good Manufacturing Practice capabilities within the broader clinical pharmacology unit in which the HCU is embedded are important from a regulatory standpoint, alongside the capability and capacity for carrying out complex procedures.

Replacing Field Studies?

There is much debate at the moment about whether challenge studies can replace field studies. Much of this hinges on the opinion of the regulators, and how that evolves. Today, challenge studies are run to generate proof-of-concept data and optimise the dose to be used in field studies; regulators do not consider them to be a replacement for a field trial. That said, there are some special cases where it can be argued that a challenge study would improve on a field trial – for example, travel vaccinations – and they might be open to consider the change. In other cases, such as an influenza vaccine, this is far less likely.

However, regulators are now starting to warm to the human challenge model. They already accept proof-of-concept challenge studies, but do not see them as acceptable as an efficacy study, other than as complementary to a field study. In the coming years, for certain specific indications where field studies are particularly difficult or slow, a challenge study might be viewed as an acceptable alternative. The fact that such a study will be run with a smaller number of patients is a drawback though, as it does not generate enough data to populate a safety database. Larger, sufficiently powered safety studies will still have to be run to pick up on potential safety problems.

The human challenge model can reduce complexity, regularise data collection, and limit the noise typically seen in fi eld-based trials, while also limiting the potential for high drop-out rates. Its standardised infrastructure gives fewer protocol violations, reduces the burden for sponsor and investigator alike, and optimises communication. A single site trial, with limited subject numbers, that gives equal powering to a multi-site study provides numerous advantages. As the science progresses, the challenge model is sure to become more widespread and expand into trials for other pathogens.

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Adrian Wildfire, Project Director, Infectious Diseases and Viral Infection Unit at SGS Life Science Services, has nearly 30 years of experience in communicable diseases. He has trained and worked within the fields of bacteriology, virology, parasitology and mycology, obtaining his Fellowship in Medical Microbiology in 1990 and a Masters in Parasitology in 1998. Adrian is the author of numerous papers and has been employed by a range of infectious disease key opinion leaders at various hospitals, academic institutions and CROs.

Bruno Speder holds degrees in Bio- Engineering and Business Economics from the University of Ghent, and has an additional degree in Health Economics from the EHSAL Management School. He joined SGS Life Science Services in 2008, and held several positions in the company's Regulatory Group before assuming his current position as Head of Clinical Regulatory Affairs. In this role, Bruno is involved in all the regulatory aspects of drug development, with a focus on regulatory support to sponsors in early development phases.
Adrian Wildfire
Bruno Speder
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