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Clinical trials for a new vaccine are intended to determine whether it is safe and effective for use in humans. Before reaching this point, a vaccine is likely to have already been in development for a number of years and undergone rigorous preclinical testing.
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Classically, clinical trials unfold in three phases in order to gather data and information about a medicine and its performance. This will form the basis of a dossier submitted to regulatory authorities by way of an application for licensure. In drug trials, Phase I usually investigates the safety profile of a new medicine in a small group (10-50) of healthy adult volunteers. Efficacy is explored in phase II when the target population (numbering 50-100) is first involved. Different dosage levels will also be explored at this stage to determine the optimum dose. Finally, Phase III takes the trial to a large-scale safety and efficacy study in a relevant patient population, usually in excess of 3,000. Contrary to popular belief, each phase of a clinical trial does not constitute a single study. More often than not, each phase will involve numerous separate trials, all aimed at generating the data necessary for further progression.
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For vaccines the progression of clinical trials differs somewhat from conventional drugs. This is because vaccines are primarily given to healthy individuals as a preventative measure while drugs are for use in patients already suffering from a condition. As such, different measures of efficacy are required. Most regularly, researchers will look for 'surrogate markers' in the bloodstream of subjects to indicate that the vaccine is working. This will involve assessing the levels of T-cells or antibodies generated by the vaccine that are capable of neutralizing the target virus or bacteria. As such, safety and effectiveness are less likely to be assessed in distinctly separate stages. Clearly, data concerning the generation of antibodies will be available right from the outset of the early-stage safety trials and it would be foolish to ignore it. The population size undergoing testing can therefore be the most significant difference as the phases progress.
If an approved vaccine already exists, comparative studies will most likely be required during phase III. When it is known that a particular level of antibodies can protect against the disease, this "efficacy marker" will become the hurdle the vaccine will need to clear before being deemed successful. However, such a marker cannot be proven in many cases, necessitating extensive field trials to assess protection afforded by the vaccine against the natural occurrence of the disease. When a large 'at-risk' target population can be identified, a vaccinated group can be compared with a control group to see if a significantly different rate of infection can be observed.
Should a human challenge model for the disease exist, vaccine development can sometimes be accelerated in a phase IIb study which allows a preliminary assessment of vaccine efficacy by comparing disease attack rates in vaccinees and unvaccinated control volunteers. These studies can be ethically justified if they are conducted by qualified investigators with rigorous adherence to a scientifically valid protocol with clear safeguards for volunteers.
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For virulent and deadly diseases such as Ebola, for example, challenge trials are an ethical impossibility. The speed of the disease's onset in remote areas also makes it almost impossible to trial a vaccine during an outbreak. It is for these reasons that the Bioshield Act in the US has incorporated an "animal efficacy rule", requiring proof of efficacy in two animal models, with phase III focusing on safety and dosage. This could speed up the vaccine development process for bioterror threats such as Ebola.
Clinical trials are a long and intensive process so that no drug or vaccine should find its way onto the market without a thorough examination of its benefits and potential side effects.
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