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The path of drug discovery

Developing a drug requires taking a long, sign-posted pathway. More than ten years separate the initial discovery of a “therapeutic target” by a researcher (protein, gene, etc. linked to the development of a disease) and the marketing of a drug. The steps of the tests and trials required before placing a drug on the market are strictly codified and regulated. They require considerable investment in terms of time and resources for all pharmaceutical laboratories.

From in vitro to in vivo

Once a target has been discovered, it is brought into contact in vitro with thousands of chemical molecules, and only a small number of the most interesting of them will be tested in vivo on animal models. The 3 to 5 most promising are then tested on humans, first on healthy individuals, then on larger and larger groups of individuals affected by the disease targeted. Thus a molecule can “stand out from the crowd”.

On the road to marketing

If the findings of all these tests and trials are conclusive, an application for marketing authorisation can be filed for the molecule with the health authorities, which will assess its therapeutic pertinence, its price and its rate of reimbursement. 

One on the market, the drug will then be monitored in the framework of its routine prescription for the entire population to regularly reassess its efficacy, its side-effects, indications, etc.

Fundamental research is the essential starting point for developing any drug. It is devoted to understanding how the organism functions, physiologically (normally) and pathologically (during a disease), to identify in detail how a disease develops and thus how it can be prevented, relieved, treated and eventually cured.

In the case of cancer, researchers try, for example, to understand how a normal cell becomes cancerous, how it escapes the immune system, how it forms a tumour, how it grows in the organism, and so forth. Immediately certain abnormal genetic, cellular and/or metabolic processes are identified they may become “therapeutic targets”.

The challenge is to find the right “arrow”, meaning a chemical molecule capable of acting on these targets (protein, cell receptor, enzyme, gene, etc.) to impede the development of the cancer.  Fundamental research in oncology is the “backbone of all innovations"*.

Fundamental research is usually performed in the laboratories of public universities.

*Cancer Plan 2014-2019

The purpose of pharmaceutical research, or drug discovery, is to identify a molecule that acts on a target discovered by fundamental research. It is proceeds in successive phases:

  1. An in vitro test is developed to visualise and measure the activity of the target.
  2. Screening is implemented. This entails bringing the target (enzyme, protein, etc.) into contact with:
  • thousands of chemical compounds held in databanks called combinatorial libraries (systematic screening),
  • or certain compounds known for their specific activity (target oriented screening).

It is also possible to seek to design a compound capable of acting on a target by using in silico modelling techniques (using computers).

  1. After identifying compounds called “hits”, or in other words compounds that have very interesting effects, new tests are performed to measure the dose-effect of the compound and verify its physiochemical properties.
  2. The molecular structure of the hits is optimised by medicinal chemistry to improve its activity on the target and its behaviour in vivo.

The purpose of preclinical trials is to evaluate a candidate drug in living (in vivo) but non-human systems. It requires performing animal experiments, most commonly on rodents: mice and rats. This is both a scientific and legal obligation as it is impossible to mimic the complexity of a living organism in vitro and it is inconceivable to test an unknown substance directly in humans. They are performed to:

  • evaluate the action mechanism of the candidate drug and measure its activity (pharmacology),
  • describe its behaviour and the fate of the substance in a living organism (pharmacokinetics),
  • establish its level of toxicity.

A patent is usually filed at this stage to protect the discovery.

Phase 1 trials are used to evaluate certain effects of the candidate drug in humans, including:

  • its pharmacokinetics: how the substance is absorbed, diffused, transformed and then eliminated by the organism;
  • its toxicity: tolerance and adverse effects are observed, in order to corroborate the toxicity pre-evaluated in animals and estimating, in increasing levels, the maximum dose possible for this substance in humans.

The tests are generally performed on small groups of healthy individuals (fewer than 100; the term “healthy volunteers” is used) over a short period and under strict medical observation in centres certified by the health authorities.

In oncology, phase 1 trials can be proposed to patients for whom the usual therapeutic resources are exhausted.

The purpose of phase 2 trials is to:

  • confirm the therapeutic effect of the candidate drug,
  • verify its optimal dose,
  • measure its possible adverse effects.

Therefore the tests are performed on patients, generally over a period covering several months. Initially, phase “2a”, the substance is tested on a relatively small group of patients (100 to 200 subjects),  then during phase “2b”, it is tested on a larger sample (several hundred) to determine the dose of the substance to be administered that is both efficacious and well tolerated.

The phase 2 trials generally compare candidate drugs with placebos to evaluate their efficacy: the patients are divided into 2 groups of which one receives the substance and the other none.  

The purpose of phase 3 trials is to:

  • compare the therapeutic efficacy of the candidate drug in comparison to the current reference and/or a placebo, especially if no therapy exists;
  • evaluate its benefit/risk ratio.

The population studied is therefore divided into two groups (sometime more):

  • one takes the candidate drug: this is the “experimental group”.
  • the other takes either the standard treatment or a placebo: this is the “control group”.

Usually, neither the patient nor the medical team knows what treatment the patient is taking. This method is known as “double blind” in order to ensure maximum objectivity.

These trials are performed on large numbers of patients, from several hundred to several thousand, generally requiring several study centres. Thus they are known as multicentre trials.

If the results of the tests are conclusive at the end of this phase, they are submitted to the health authorities so that the candidate drug can be marketed. This stage is called AM (Marketing Authorisation). The industrial development of the drug is usually carried out in parallel with the clinical trials.

The pharmaceutical companies that have carried out the clinical trials from phases 1 to 3 and obtained positive results will aim to produce the compound industrially and market it in the form of a drug. To do so, they must gather all the data of their trials in an application for Marketing Authorisation (MA).

The MA is issued by the competent European authorities (the European Commission, in line with the recommendation of the European Medicine Agency - EMA) or national authorities (the National Drug Safety Agency - ANSM in France).

The MA file has an internationally uniform structure to facilitate its evaluation by the authorities. It describes three key aspects:

  • quality: data linked to the industrial fabrication of the drug (production of raw materials and the finished product, fabrication process reproducibility controls).
  • safety: data of the study performed during preclinical development (toxicology, pharmacokinetics, etc.); 
  • efficacy: results of clinical studies on healthy humans and patients, with a positive benefit/risk ratio.

The MA is also associated with the Summary of Product Characteristics (SPC), the patient information leaflet and information on labelling.

Different marketing authorisation procedures are possible: 

  • centralised: the file is registered at the head office of the EMA for an authorisation valid for all European countries;
  • mutual recognition: the file is registered with the competent authority of a Member State and can then be extended to other countries;
  • decentralised: the file is registered at the same time in all the Member States and the authorisation is issued by a reference State.

Temporary Authorisation for Use (TAU)

Exceptionally, a drug intended to treat a serious or rare disease can be made available in large hospitals before its MA, in the case of emergency or in the absence of any other appropriate treatment.

In France, the MA file is submitted to the Commission on Transparency of the Executive Health Authority, which issues its opinion on the therapeutic value and on the improvement of therapeutic value that the drug offers to patients with the disease targeted. The price of the drug is set by the Economic Commission on Health Products (CEPS) and its rate of reimbursement, by the National Health Insurance Fund  (UNCAM).

Phase 4 (or post MA) entails the long-term monitoring of a drug after it has been placed on the market in order to detect rare side-effects and latent complications.

Indeed, during the clinical trials prior to the Market Authorisation (MA), a small number of patients are treated in comparison to the tens or hundreds of thousands or people liable to take the drug once it has been placed on the market, and the effect of the drug is observed for a short time. This does not allow, for example, the detection of:

  • rare effects,
  • toxicity linked to chronic use,
  • use by elderly persons, pregnant women, and women who breast feed;
  • interactions between drugs, etc. 

The risks linked to the drug must therefore be monitored and measured by the pharmaceutical laboratories in the framework of their routine prescription, under “real life” conditions.  Such companies are obliged by law to set up a pharmacovigilance department. The latter must process all the information on adverse effects linked to the drug, whatever the origin, and report them to the health authorities. In the case of a risk to the patient’s health, the health authorities may restrict the use of a drug, modify its indications, or even demand its withdrawal from the market.

Since 2011, pharmaceutical laboratories have been obliged to carry out post MA studies on efficacy and safety.