Phase 4 clinical trials: everything you need to know!

Published Aug 9, 2021 • By Aurélien De Biagi

Having spoken about clinical trials and more specifically about the legal framework and the first three phases, today we provide you with an article on phase 4. The latter will be conducted after the marketing authorisation until it is withdrawn. In this article, you will find out what phase 4 is in detail as well as the way in which drugs are monitored after they are first released.

If you would like to find out more, take a look at our article!

Phase 4 clinical trials: everything you need to know!

What is phase 4 of clinical trials?

First of all, once preclinical trials (on animals in a laboratory) have produced satisfying results, the clinical trials can begin. These clinical trials are conducted in 4 phases, here is a reminder of the first 3:

  • Phase 1 is designed to measure the toxicity of the drug in a small group of healthy volunteers.
  • Phase 2 measures the tolerance and effectiveness on sick volunteers.
  • Finally, phase 3 assesses the benefit/risk balance of the drug.

if you want to know more about these trials, take a look at the following articles:

Phase 4 clinical trials begin once the drug is marketed. It has several objectives, namely:

  • Identify undesirable effects (pharmacovigilance);
  • Refine, extend, minimise and modify the therapeutic indications of the product;
  • Evaluate the risk and effectiveness of the treatment of large populations in a real use situation (outside the controls of clinical trial);
  • Conduct pharmaco-economic studies (the evalutation of costs and effects of a product).

The methodology of phase 4 studies differs largely from that of other phases. In fact, in this case, it concerns an observational study and no longer experimental. Since the drug is now on the market, it is used without any control on the part of the methodologist who can only examine results obtained.

This system can evaluate the effectiveness of the drug in real-life situations, refine the rare undesirable effects (pharmacovilance) but not only this. In fact, phase 4 studies also allow for new therapeutic indications or new formulations to be found (appearance of the drug: capsule, intravenous or intramuscular injectable, etc.). Pharmacovigilance plays a crucial role in this phase and in this study of the drug throughout its life. It enables the drug to be monitored and to ensure its safety (absence of toxicity) because unfortunately, in very rare cases, all may not be seen in previous phases of clinical trials.

What is pharmacovigilance (PV)?

Pharmacovigilance lasts the whole duration of the drug's existence. It begins at the time when marketing of the latter occurs and ends during its withdrawal from the market. It is known as post-AMM (marketing authorisation). The main objective of PV is determining rare or long-term undesirable effects. In fact, during earlier phases (phases 1, 2 and 3), volunteers are selected according to specific inclusion and exclusion criteria. Therefore, the objective is to obtain the most homogenous patient sample possible so that data is statistically relevant. Furthermore, trials are made in optimal monitoring situations (limited duration, hospital facilities, etc.) When marketing the drug, the latter is much more widely specified making it possible for unknown and unexpected effects to appear.

Any serious adverse reaction (putting life in danger or the cause of disability or hospitalisation) or not, known or unknown, must be submitted to the pharmacovigilance regional centre (PVRC). Any health professional must raise the observed adverse reactions to their nearest PVRC. However, their declaration is not limited to health professionals. In fact, patients and patient associations may also make reports of pharmacovigilance on the FDA website for safety information and adverse event reporting program.

Following a pharmacovigilance report, the PVRC sends an account to the Medicines and Healthcare products Regulatory Agency (MHRA) who can then take appropriate action: alert health professionals, withdrawal from the market, change of indication, etc.

What event leads to the development of pharmacovigilance?

In the 1950s, a molecule known as "thalidomide" arrives on the market. This drug is used as a non-barbiturate sedative. Showing few side effects during the tests carried out at the time, thalidomide become the sedative molecule of choice. It is also used in women and particularly in pregrant women to relieve the suffering of nausea during pregnancy. However, some years after its introduction onto the market, doctors throughout the entire world reported some undesired effects during thalidomide use. These undesired effects could range from the absence of a finger to that of one, of several or even of all newborn limbs whose mothers were taking this treatment during pregnancy. Thalidomide withdrew from the market and its teratogenic effect (producing deformities in the unborn child) was revealed. According to current estimates, around 10 000 to 15 000 children would have suffered the teratogenic effects of thalidomide.

Tests carried out in the 1950s on thalidomide did not meet the same requirements as current clinical trials. In fact, it had been tested on rats, species for which thalidomide does not have undesirable or teratogenic effects. For this reason, thalidomide was able to be marketed and administered in pregnant women. This health scandal (one of the most serious) has triggered a pharmacovigilance organisation leading to what we know about it today: a systematic report of any observed adverse reactions.

Today, thalidomide is still used. In fact, it has, subsequently, proved its effectiveness in the treatment of certain diseases such as leprosy, systemic lupus erythematosus and certain cancers for example. The prescription terms of this molecule are of course stricter at the current time. In fact, in order to be able to prescribe thalidomide in a woman of childbearing age, the latter must fulfill certain conditions. For example, an effective contraception before the start of treatment, the whole way through treatment and 4 weeks after its end must be introduced. A pregnancy test must also be provided every 4 weeks during treatment using thalidomide

In addition, thalidomide passing in the sperm, men treated must, among others, make sure to use a condom during sexual relationships with a woman of childbearing age or who is pregnant.

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avatar Aurélien De Biagi

Author: Aurélien De Biagi, Health Writer, Pharmacy Student

Aurélien is a fifth year PharmD student at the University of Lorraine in France and writes health articles for Carenity. He is particularly interested in the neuropsychiatric and cardiovascular fields.

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