Clinical trials: always looking after our health

Sandra Domínguez Manchola · 15-10-2020 10:00 · Science Chronicles

Let's start at the beginning. What are clinical trials? These are clinical studies that have the purpose of evaluating the effectiveness and safety of medicines, medical devices for human use (for example, a pacemaker) and even new surgical techniques. Clinical trials are meant to ensure the well-being of the patient and, in order to preserve it, a number of rules set by law in a given country, ethical codes or Good Clinical Practices are to be complied.

In this post we are going to focus on clinical drug trials. Before research can be conducted on humans, prior preclinical research is essential, both on cell culture and on experimental animals. Thanks to this basic research, extensive knowledge and data about a drug can be obtained: from its proper discovery and knowledge of its physicochemical properties to its biological characteristics. Before making the leap to human experimentation, it is previously indispensable to have conducted experiments on animals that not only prove the effectiveness of a drug, but also provides information on the number of doses, mode of administration (oral or into a vein / intravenous, for example) or possible adverse effects.

The information thus obtained in the laboratory is incorporated into a written report so that a permit can be requested from the regulatory authorities and ethical committees of a given country, the Spanish Agency for Medicines and Health Products (AEMPS) and the Ethical Committee for Research with Medicines (CEIM) in the case of Spain, for instance. These authorizations must always be requested when a clinical trial is to be conducted. As far as the human experimentation is concerned, we may break down clinical trials into the following phases:

  • Phase I: studies focus on determining the pharmacokinetics (that is, how the drug behaves in the body: how it is absorbed, how much it degrades, what percentage of it reaches the organ to be treated...) and safety of the drug, which in turn will allow to calculate the safe dose range and the tolerated dose range, using the data obtained in animal experiments as a starting point. These studies involve a low number (approximately 20 subjects) of mainly healthy participants, as it is much easier to distinguish side effects in healthy than in sick people. In certain therapeutic areas such as oncology, volunteer patients are recruited because this type of therapy is very toxic in itself (otherwise, it would not be able to deal with tumor cells), and thus it would be unethical to administer it to healthy volunteers, who, in addition, would develop so many adverse effects that the therapy would never move to phase II.
  • Phase II: these studies are carried out in sick patients in the search for appropriate dosage (as defined within the ranges in phase I) and in order to collect the first data on its efficacy (that is, on whether the drug, when administered in safe dosages, improves the health of patients or not). In these studies, the number of participants is increased as compared to the previous phase (from 80 to 100 subjects) to ensure that the curative effect is not the result of chance.
  • Phase III: at this point, just before the drug is marketed, the number of participating patients is considerably increased (between 200 and 300), being a more heterogeneous sample as compared to phase II. What is sought now is to determine the efficacy and safety of the drug in a large group of patients that may best reflect the variety of ages, gender, previous illnesses (among other factors) a doctor treating such illness would encounter on a daily basis.
  • Phase IV: the studies in this phase are conducted once the drug has been authorized and marketed. These trials count on a high number of participants (more than 1000). Long-term efficacy is studied; monitoring is performed in order to find our whether further adverse effects appear, doses are reviewed, as, in short, the risks, benefits and optimal use of the drug.

Approximately 10 years elapse from the discovery of the drug to the completion of phase III. Once phase III is finished, the authorization and registration for the commercialization of the product, which may take up to 1-3 years, will proceed.

It should be born in mind that during this long period, and in each of the above stages, a large percentage of the drugs being developed are discarded as they fail to be safe or effective enough for humans. It is estimated that only 1 out of every 5,000-1,000 compounds that begin the drug discovery and development process, will be actually approved for use in patients (see Figure).

As we have seen, the drug we bought at the pharmacy, now in our "medicine cabinet", had to go through a very long process that required it to be good, effective and safe for our consumption, and also to out-compete many other drugs throughout each one of the phases, thus turning to be the winner ... Long live the drug!

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