The life cycle of a molecule is from invention to generics
Updated: Aug 16, 2019
All new molecules must pass these steps. It costs billions. Why?
Not one, even the most promising medicine, can get into the pharmacy “directly” from the laboratory. Medical history knows many cases, even from the late history of the 1960s, when drugs were put on the market without going through a comprehensive study - and there came tragedies like famous Thalidomide tragedy.
Nowadays, medicines must undergo all relevant procedures according to a clear protocol. It is always long (up to 20 years) and expensive.
At the beginning of a long journey, it is never clear whether the work will succeed, and which one, but thousands of laboratories and hundreds of thousands of scientists begin work every year.
The success of creating a medicine will be the unpredictable component of enormous scientific work, patience, researcher intuition, investment and, finally, good luck.
In this article, we will describe how the tests pass, using the example of our Calix.
At the very beginning there is a target - a goal for which a medicine is created. But it may well happen that the formula is synthesized by chance - and then they search for the target. The formula can be "rediscovered" - having found significant flaws in the old formula, because of which it was removed from the race, and optimize it. Drag designers work on the molecule. Special programs make it possible to verify its chemical properties even at the stage of the electronic model. And, if these properties prove to be interesting for further development, and the molecule can chemically exist, it is synthesized in special laboratories and subjected to the first studies of its properties. At this stage, a huge number of molecules are produced.
Then, if the chemical properties turn out to be as expected, the action of the molecule begins to be studied on the selected cells. This is the so-called IN VITRO. In the case of Calix, on cancer cells in a laboratory setting. And if the expected action is confirmed (and at this stage, approximately 70% of all developments will be screened out), the molecule gets into further study.
It is necessary to register Preclinical studies, which are carried out according to strict international protocols for several years. Their goal is to prove the effectiveness and non-toxicity of the drug on living things. This is the very stage of IN VIVO. As a rule, two types of animals are used for this stage of research - rodents - the famous laboratory mice, and non-rodents, no less famous experimental rabbits. For animals, strict ethical standards are currently being applied that do not allow unnecessary suffering and unjustified experiments.
At this stage, it is necessary to select the dosage, route of administration, find out what happens to the drug in the body of a living creature, does it provoke cancer and other pathologies, how it interacts with other drugs, what happens to pregnant females and offspring. All data is collected and carefully analyzed.
Unfortunately, at this stage most of the new drugs are screened out - most are prohibitively toxic - that is, toxicity exceeds the expected benefit of the drug. And, if it is not possible to find ways to reduce toxicity, the molecule leaves the race, and all the previous long-term work and financial investments can be considered failed. Negative experiences are summarized and published for the scientific world.
Great luck for scientists and test sponsors (and maybe for all mankind) if the drug proves its non-toxicity and effectiveness in relation to the declared target.
So, for example, what happened to our Calix. The drug was effective against cancer cells in living models, and non-toxic to them even in high concentrations.
Preformulation studies are carried out - in what form of administration should the drug be used? What will be the period and conditions of its storage? It is necessary to find the optimal characteristics.
Ahead is the most responsible, ethically complex and expensive part of the trials - human trials:
At the first stage of clinical trials, it is necessary to prove the toxicity of the drug and its effectiveness in humans. Find out where the drug gets after administration, how it affects all body systems, how it is excreted (pharmacokinectics). This stage is preceded by a huge preparatory work. For a clinical trial, it is necessary to obtain permission from regulatory authorities, prepare research protocols, prepare research bases, work with doctors and staff, and prepare insurance contracts.
To do this, the research center recruits from 25 to 100 healthy volunteers, usually middle-aged men who are in good physical and emotional shape. People must be informed about all the known properties of the studied drug. The studies are carried out with all possible precautions regarding patients, only in the conditions of equipped clinics for several days, all participants in the experiments are insured and are under round-the-clock supervision of highly qualified personnel. These studies are generously paid and very often volunteers become serial. This stage takes about 1.5 years and costs significant funds.
If the goal is achieved, the drug has proved its non-toxicity, reliable data on acceptable dosages, side effects, pharmacokinetics have been obtained, a report on the test is sent to the prescriber. Permission to receive further human testing is required.
Next, it is necessary to conduct the second part of clinical trials - already on people suffering from a specific disease. For this, several research centers are selected, usually international. All work must be carefully prepared and well coordinated. Subjects are informed about the tests, they have the opportunity to familiarize themselves with the documentation, obtain information about the drug from their doctor and express their consent to participate in the tests. Typically, approximately 1,000 people in several centers participate in these trials. Some of them receive a new drug, some are already known and used in medical practice, and some can receive placebo. All data is carefully collected and processed.
This stage of research is also expensive, difficult to organize and time consuming. If the drug is rejected, then the loss of time and money for companies becomes very significant.
The third stage of research is conducted on a very wide selection - up to 5000 people around the world.
And only after a thorough analysis of all the data, receiving reports from all centers, documents about the drug are submitted to the centers for approval. In the USA it is the FDA, in Europe it is the EC, and in Russia it is the Ministry of Health.
Then comes the period after clinical observation.
Calix is in the middle of the road, but we have high hopes for him.
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