In the EU, clinical trials have a regulatory definition: “Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the objective of ascertaining its (their) safety and/or efficacy”.
The exact nature of these pre-registration trials will depend on a number of factors including the drug itself; the particular disease or indication it has the potential to treat; and the patient group studied.
Trials may be segmented into four distinct phases although there is commonly some overlap between them. The terminology for participants reflects the particular phase: Phase 1 typically uses healthy volunteers (‘subjects’) while later phases involve volunteers who have the disease in question (hence ‘patients’, or ‘patient volunteers’ in some cases). This page provides a brief overview of Phase I, II, III and IV trials and why they sometimes overlap.
Phase I represents the first use in humans, with studies involving healthy volunteer humans as opposed to animal models. The aim is to begin to establish the safety profile of the drug in question, determining the potential for both beneficial and adverse effects. The studies examine the pathways through which the drug is absorbed, distributed in the body, metabolised and eliminated and the maximum tolerable dose. They can also study proposed formulas and dosage (frequency and scheduling) for further trials. The primary focus is on safety rather than efficacy, with studies usually lasting only a few days or a few weeks. Phase I studies might typically require 12 months to complete and involve comparatively few subjects. Serious Adverse Events (SAEs) are relatively rare and every effort is made to minimise any risk to the participants. For some drugs known to be toxic (such as those used in the treatment of cancer) Phase I studies in healthy volunteers may not be possible for ethical reasons.
These trials aim to study the drug as administered to patients who already have the disease which the drug may have the potential to treat. The objective is to determine the optimal dose and dosing regimen, one which delivers maximal efficiency alongside acceptable adverse effects. Phase II trials may also investigate metabolism and excretion in more depth and establish safety and efficacy markers for subsequent trials. The scale is larger, running up to hundreds of patients, lasting several weeks or months and often uses a double blind design where a standard of care comparator product or placebo is used to benchmark the investigation product’s safety and efficacy.
This phase usually involves hundreds or even thousands of patients and may require several years for completion. The ultimate aim is to gain statistically significant scientific proof of a positive benefit-risk profile of the medicinal product which is required for regulatory approval and often the favoured design is again double blind with randomised allocation of patients to receive active drug or placebo or active comparator treatment. It will depend on the drug and disease as to whether the current standard therapy is used as a comparator for the results, or whether they are compared to a placebo. If a serious disease for which there is already an effective treatment is being studied, the new drug may be given in addition to the established treatment, to determine if it can increase the effectiveness, compared to patients receiving placebo in addition to the established therapy. There is no guarantee that any trial in this phase will result in a Marketing Authorisation (MA) and naturally the oversight of an effective pre- and post-marketing pharmacovigilance system is a critical component of any application for an MA.
Different types of studies can be included in phase IV, which is conducted following the granting of a Marketing Authorisation (MA). The drug has often been placed onto the market (although there are cases this does not always happen directly after authorisation). However, regulators do often require some type of Phase IV studies (or in EU parlance, “post-authorisation studies”) to be conducted within a timely manner once a drug does go on sale. This may be to clarify issues which were not resolved during Phase III but that regulators did not classify as a cause to delay marketing. Size and designs can vary, sometimes consisting of classical clinical trials, sometimes epidemiological studies studying large populations using databases or registries of treated patients.
In practice, classic Phase I studies may investigate far beyond the initial dose findings, with escalation studies over several years taking place during the ensuing phases. Or, in certain cases, a company will apply for approval to mount a combined Phase II – III trial, should the results from initial larger scale Phase II trials prove suitable.
From a pharmacovigilance perspective, larger scale studies are preferable to more fully establish the safety profile of any particular drug. However, there are inevitable limitations to a pre-registration clinical trial programme. Thus, for example, the studies do not usually include sufficient patients to identify uncommon or rare adverse reactions; the close monitoring that occurs in a clinical study, with careful attention to inclusion and exclusion criteria and co-administered medicines, does not mirror real life post-marketing; the frailest patients and various populations (e.g. women, ethnic minorities) may be under-represented; and the duration of treatment may be limited. Thus there is a need for pharmacovigilance after a medicine is marketed – comprising spontaneous reporting and review of suspected adverse reactions but also increasingly, a requirement for post-authorisation safety studies (PASS) and other post-authorisation studies. In the EU, PASS are defined as: “Any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures”.
It should be noted that the information here does not constitute any formal advice on pharmacovigilance nor other professional advice.
For more information contact PrimeVigilance today.
 Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use
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