Approval of a drug

Any drug that reaches the patient is subjected to a rigorous process which evaluates its safety, efficacy, and benefit in treating one or more medical conditions. In today’s article, we will go through the steps that constitute the approval of a new drug from its discovery to its administration in real life situations.

From test tube …

All drugs currently approved go through two important stages in a process that can take up to 10 years and cost about $ 1 billion /new drug approved.

The first stage is called the “pre-clinical” development period and the second step is the “clinical phase”. In the first phase, called the “bench stage”  screening experiments of several hundred or even thousands of molecules are done to identify possible therapeutic effects that these molecules might have (eg. anti-inflammatory, anti-viral, hypoglycemic, etc.). These effects are first tested on specific cells (ex. hepatocytes, adipocytes, muscle cells, etc.), depending on the sought-out effect and the possible target of the drug.

Once identified, tens or hundreds of “candidate substances” that meet certain criteria (safety and therapeutic effects) go in the second stage of pre-clinical studies: studies on laboratory animals. In this phase, the safety and efficacy of the substances are assessed in vivo (more complex organized living organisms). These effects are heavily dependent on the systems used (a substance does not have the same effect in a cell line and / or an animal model and / or human subjects).

Using these intermediate stages and a linear progression (from a simpler organism to a more complex organization; cell line to animal and then to humans) a series of safety nets are set in place to detect possible toxic effects and to rule out drugs that are not efficient.

Studies in humans

Typically, out of hundreds of substances tested on animals, only a few (usually one) go into the second phase, the clinical trials phase.

To be able to be administered to human subjects, drug candidates must first demonstrate a good safety and therapeutic profile. Clinical trials are strongly regulated and there are limiting steps put in place to avoid possible errors that could endanger the health and lives of patients.

There are 4 phases of clinical trials (named phases I to IV) and, as with the preclinical phase, it follows a logical progression in terms of therapeutic effects and toxicity testing.


Fig. 1 Thousands of researchers from the medical and pharmaceutical communities continuously develop medicines that treat hundreds of millions of patients worldwide each year.

Phase I

Phase I is also called “the first in human” clinical trials since it is for the first time in the development sequence of the substance that it is administered to human participants. In this phase only healthy participants receive the drug (although in the case of some oncology drugs that are urgently needed, healthy participants are replaced by patients). In phase I clinical trials, the optimal dose is determined as well as the safety profile of the administered substance. Usually, the number of participants in this phase is around a few dozen individuals. Phase I trials is where many drugs end their development progression because of a bad safety profile or unexpected side-effects.

Phase II

In phase II trials a larger number of participants (several hundred) are recruited. In this step, the drug is administered to patients with the disease for which the drug was developed. This is the “do or die” stage since in these clinical trials the drug will prove its ability (or inability) to become a new weapon in the doctor’s therapeutic arsenal. Approximately 1 in 5 substances advances from phase II to phase III trials. 

The substance is stacked-up against either the “standard of care” (SOC) or a placebo to assess its efficiency and intrinsic therapeutic effects. The Food and Drug Administration (FDA) recommends that all new substances be tested in comparison with a placebo to demonstrate its intrinsic therapeutic effect.

Phase III

If a drug candidate has reached phase III clinical trials, it means that it has good a very good potential to be approved. It has a good safety profile and good therapeutic effects in treating the given disease. In phase III trials there is a sharp increase in the number of patients recruited for the studies in order to see the effect the substance has on large groups of patients. This will help identify possible side-effects with low prevalance.

Clinical research teams are created in different locations around a country, continent or the world. These teams start clinical which bring very important results related to the efficacy and safety profile of the drug in broader clinical conditions.

1 of 2 substances which are being tested in phase III will not be approved for use. The largest sums of money are spent in this phase of clinical research. It is estimated that a large sponsor (large pharmaceutical company) will spend on average around 450 million US dollars for a drug in Phase III clinical trials, while a small sponsor will spend around 15 million US dollars for each tested drug. These sums depend on the number of centers included in the survey, the number of patients recruited, duration of follow-up of patients (in some cases, in chronic diseases, patients should be monitored for a longer time to be able to observe a therapeutic effect). If a drug proves itself in phase III clinical trials, it will be approved for use in patients.


Fig.2 The phases of clinical trials, the number of participants and their objectives.

Reproduced from:

Phase IV

After the drug is approved for us on the pharmaceutical market, its safety profile and effectiveness needs to be followed for at least 2 more years to make sure that it is safe and to gather more real life data.This phase is also called the post-marketing phase. There are some famous cases of substances that successfully passed the first 3 phases of clinical trials, but which, when administered to large groups of patients in real life settings proved to have side-effects with disastrous consequences (ex. Rofecoxib, Rosiglitozone, etc.) 


Under certain conditions, some drugs which have already been approved may be re-approved for other diseases, skipping some steps in this process, becoming more readily available to patients.


All stages of clinical trials are heavily regulated and monitored by specialized organizations (EMEA for Europe and the FDA for the USA) ensuring that only safe and effective medicines will be used by patients.




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