Clinical trials are studies that are intended to discover or verify the effects of one or more investigational medicines. Testing an experimental drug is a lengthy process, usually lasting several years.
Before pharmaceutical company starts clinical trial on a new drug, it conducts extensive pre-clinical tests. These experiments involve both “in vitro” (test tube or cell culture) and “in vivo” (animal) testing using wide range of doses of the experimental drug to obtain preliminary information about drug efficacy, toxicity, distribution and elimination. Such tests help a pharmaceutical company to decide whether the experimental drug has scientific merit for further investigation or not. However, no animal is sufficiently similar to humans and therefore the experimental drug must be tested also on humans.
The overall procedure of clinical testing is commonly classified into four stages, usually called phases.
If an experimental drug successfully passes through phases I, II and III, it will usually be approved by a national regulatory authority for use in general population. Phase IV is a “post-approval” study.
The goal of testing in non-human subjects is to gather information about efficacy, toxicity, distribution and elimination of an experimental drug. Some testing can be carried out by means of computer modelling and by isolating cells and tissue, but subsequent tests on animals are necessary and represent an obligatory stage in the process of obtaining regulatory approval for a new drug. In order to protect the well-being of research animals, researches are guided by principles which reduce the number of animals to a minimum, the effect on the animal is minimised and the animal welfare is improved.
Clinical testing on humans consists of four stages (literally Phases I, II, III and IV). Each phase has specific objectives and the number of people involved increases as the trial progresses from one phase to the next one.
The overall aims of the phases are as follows:
- Phase I: to assess safety of a drug on healthy volunteers (first in humans)
- Phase II: to check the efficacy of a drug on patients (proof of concept)
- Phase III: to assess how effective the drug is compared to the gold standard treatment
- Phase IV: to study the long-term effects of a drug (postmarketing surveillance)
Phase I Trials
Before beginning a Phase I trial, the sponsor must submit an experimental drug application to the regulatory agency such as European Medicines Agency (EMA), detailing the preliminary data on the drug gathered from pre-clinical studies. Phase I trials are designed to test the safety, side effects, best dose and formulation method for the drug.
Normally, only a small number of healthy volunteers are recruited. These trials are usually conducted in clinics, where subjects are observed by full-time staff. Phase I trials include dose ranging (dose escalation) studies, so that the best and safest dose can be found and to discover the point at which a compound is too poisonous to administer. The tested range of doses is usually a fraction of the dose that caused harm in animal testing. As mentioned above, Phase I trials most often include healthy volunteers. However, there are some circumstances when clinical patients can be enrolled into Phase I trials, such as patients who have already tried and failed to improve on the existing standard therapies.
Phase II Trials
Having demonstrated the initial safety of the experimental drug (often on a relatively small sample of healthy individuals), Phase II clinical trials can begin. Phase II studies are designed to explore the therapeutic efficacy of a drug in people who have the condition that the drug is intended to treat. They are sometimes called as therapeutic exploratory trials and tend to be larger scale than Phase I trials.
Phase II trials are sometimes divided into Phase IIA and Phase IIB. Phase IIA studies are usually pilot studies designed to demonstrate clinical efficacy or biological activity (“proof of concept”) while Phase IIB studies look to find optimum dose at which the drug shows biological activity with minimal side-effects (“definitive dose-finding”).
The safety assessment carried out in Phase I can be repeated on a larger subject group. As more subjects are involved, some may experience side effects which none of the subjects in the Phase I experienced. The researchers aim to find out more about safety, side effects and how to manage them. Phase II trials can be randomized clinical trials which involve one group of subjects that is being given the experimental drug and others that are receiving a placebo (dummy pill).
If researchers have adequately demonstrated that the experimental drug is effective against the condition for which it is being tested, they can proceed to Phase III.
Phase III Trials
Phase III trials are the last stage before clinical approval for a new drug. Such studies are carried out on a much larger scale than those previous two phases and are often multinational. Phase III trials are designed to assess how effective and safe the drug is for use in the patients in the target group in comparison with standard of care.
They may compare standard treatment with:
- a new treatment
- different doses of the same treatment
- having the same treatment more, or less, often (different frequency)
- a new way of giving a standard treatment
Sometimes Phase III trials involve thousands of people in many different hospitals and even different countries. Most Phase III trials are randomized. This means the people taking part are put into treatment groups at random.
Regulatory authority, such as European Medicines Agency (EMA) reviews results from Phase III trials when considering a drug for approval.
Phase IV Trials
After previous successful phases of clinical testing and after the treatment was approved by regulatory authority, there may be a Phase IV trial to assess the long-term effects of the drug or to study the impact of another factor in combination with the treatment, e.g. the drug may not have been tested for interactions with other drugs or on certain population groups.
The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer period of time than it was possible during the previous phases of clinical testing. Usually, such trials are sponsored by pharmaceutical companies and described as “pharmacovigilance”. Phase IV trials are not as common as other types of clinical testing because they are not necessary for marketing permission. However, in some cases, the regulatory authority grants restricted or provisional marketing authorization, which is dependent on additional conduction of Phase IV trial.
Who can participate in a clinical programme?
All clinical trials have guidelines about who can get into the programme. Guidelines are based on such factors as age, type of disease, medical history, and current medical condition.
The factors that allow participant to be enrolled into a clinical trial are called inclusion criteria and the factors that keep patients from participating are called exclusion criteria. It is important to note that the criteria are used to identify appropriate participants and keep them safe. The criteria help ensure that researchers will be able to answer the questions they plan to study.
Clinical trials are necessary to achieve progress in cancer therapy and provide a possibility for patients to be treated by potentially more effective treatment.
Romančík Martin, MD, PhD, MPH
Hospital of St. Cyril and Methodius Bratislava