Clinical trial safety is an important part of pharmacovigilance. Each medicinal product needs to have completed each of the pre-marketing clinical trial phases to the satisfaction of the regulatory authorities, having established an acceptable evidence base for safety as well as efficacy.
The precise nature of the pre-registration clinical trials depends on numerous factors, which will include the nature of the medicinal product itself. It also depends on which disease or clinical indication it is hoped that the medicinal product could eventually treat. The nature of the relevant patient group will also be an important factor. There are four separate phases of trials within the EU, although it is usual to find that there is some overlap between them in terms of real life practice. Phase I trials are conducted using volunteers who are typically healthy people, who are referred to within the literature and official documents as the trial ‘subjects’. All the later trial phases will involve volunteers who have been diagnosed with the disease for which the medicine is an intended treatment. These individuals are accordingly referred to as ‘patients’, or possibly as ‘patient volunteers’. This article introduces some of the key concepts that characterise Phase I, II, III and IV trials as well as brief information on why there is sometimes an overlap between them.
Phase I Studies
The first of a series of studies, these will be the first time that the responses of healthy human volunteers will have been studied as opposed to animal models. At this stage, the goal is to establish what the medicinal product’s safety profile is, identifying its potential for beneficial or adverse effects. Investigations focus on the pathways of absorption and distribution within the body, and the way the drug is eliminated. The maximum tolerable dose is also established. There may also be examination of potential dosages and formulas (scheduling and frequency) with a view to the next steps in the trial process. The key goal here is drug safety rather than considerations of efficacy. A typical timescale could be around 12 months, involving maybe 100 subjects. The incidence of Serious Adverse Events are relatively rare during this phase, all possible efforts are made in minimising potential risk to subjects. It is important to note that for some drugs (for example, certain medicines used to treat cancer) the known toxicity of that drug may mean that studying it with healthy volunteers is simply not ethically viable.
Phase II Studies
The goal at this step is to study the medicinal product when administered in patients already diagnosed with the precise disease it is hoped that the product will offer treatment for. Objectives include establishing optimal dose / dosage regime, delivering the maximum possible benefits with the minimum tolerable adverse effects. Phase II trials can also continue the examination of rates of excretion and metabolism in order to establish the important efficacy and safety metrics required in later studies. The number of participants is typically far larger than Phase I studies, with possibly hundreds of patients recruited. The studies may last for weeks or months, and a typical study would be double blinded in design.
Phase III Studies
During this phase, patient numbers in the hundreds or thousands will participate, and the timescale can stretch into several years for the study to be completed. With phase III studies the ultimate goal is to attain regulatory approval to allow the drug to reach the market. A typical study design will be double blinded, with patients receiving randomised allocation of either the drug and or a placebo. The use of placebo versus drug being studied will depend upon the drug itself, and on the particular disease. It may be the case for serious diseases for which there are already effective standard treatments established, that the standard treatment becomes the comparator instead of a placebo. It may be the case that for a serious disease, the drug being investigated is studied as an addition to that standard treatment. This will partly be for ethical reasons (it is unethical to leave patients untreated) but also to ascertain whether the drug being studied has the ability to make the standard treatment more effective when compared to patients who have received the standard therapy and a placebo. At this stage, no guarantee can be given that any given trial will result in the granting of a Marketing Authorisation (MA). The provision of an effective pre-marketing and post-marketing pharmacovigilance system would naturally be crucial for any MA application.
Phase IV Studies
Phase IV can accommodate different types of study, conducted once the drug has been granted an MA. Often the drug will have then been released onto the market, however it is worth noting that this is not always the case. Nonetheless, once the drug does go on sale, the regulatory authorities often stipulate that some form of Phase IV studies take place within a timely manner. Within the EU, these particular studies are termed “post-authorisation studies”. This may be because there are issues remaining which could not be clarified during Phase III, the nature of which the regulators did not consider to warrant a delay in marketing. The designs and sizes of these trials can be variable. Sometimes they can follow the classic format of clinical trials; others can be epidemiological investigations studying larger populations using patient registries (maintained lists of treated patients) or appropriate databases.
Why Do The Phases Overlap Sometimes?
It is possible that a ‘classic Phase I study’ could investigate beyond initial toxicology and dose findings, for example, through escalation studies which take place during the later phases. Another possibility is that a pharmaceutical company applies for approval to launch a joint Phase II – III trial following suitable results from initial Phase II studies.
Within pharmacovigilance larger scale studies would be preferable since they allow for a more comprehensive establishment of the safety profile of the drug in question. There are inevitable limitations to pre-registration clinical trial programmes. An example could be that studies do not commonly include sufficient patient numbers to identify adverse reactions which are uncommon or rare. Another example could be that the close monitoring which characterises clinical studies may not reflect post-marketing reality. Yet another could be that the more frail patients in the population or various groups are under represented such as women or patients from ethnic minorities. Or it could be that the duration of treatment may be limited. These factors are some of the many reasons why there is a need for post marketing pharmacovigilance – spontaneous reporting and review suspected adverse reactions. Increasingly regulators demand post-authorisation safety studies (“PASS”) in addition to other forms of post marketing studies. This brief overview is intended solely as an introduction to key concepts for the non-professional reader; please note that it is not any form of medical, legal or other professional advice.
