The launch of a new pharmaceutical product is a long, complex and multi-stage process. One of the longest stages in the creation of a drug is a study of its safety. Research can last up to 10 years and require large budgets to conduct it. One of the first stages of safety studies is preclinical studies, which allow us to determine the general toxicity of a substance obtained as a result of a scientific search.
What it is?
These are, first of all, safety measures taken during the development of a medicinal product. Also, during the preclinical study, toxicity and pharmacokinetics (the mechanism of movement, distribution and elimination of the drug from the body) of a potential medical device are studied.
Often the definition of preclinical studies is replaced by the identical "preclinical". However, it should be clarified that the preclinical stages of development include not only initial studies, but also the process of finding the formula of the active substance and creating the right dosage form for it. That is, preclinical studies are extremely important, but still not the only aspect of preclinical work.
Types of preclinical studies
The study of general toxicity goes through several ways at once:
- Modeling on a computer. This allows you to make forecasts based on information about the chemical structure of a substance and its properties obtained in the search process.
- Laboratory research. They include testing the safety of a future drug in cell cultures. Most people imagine preclinical studies of drugs precisely as tests outside the body. In order to centrally conduct various toxicity checks, pharmaceutical companies and the state organize specialized production facilities. It is the preclinical research centers that are the main research structures conducting such tests. But the longest way is, of course, animal testing.
- Toxicity studies on living organisms, i.e. animals. Plants are also used, and in rare cases, drugs are tested in humans.
To create complex drugs for the treatment of severe human diseases, all the opportunities for preclinical and clinical studies are used. Therefore, verification of the safety of the substance at the initial stage is done on all three components of the research process.
What security aspects are being investigated?
The manufacturer of both the new drug and generic seeks to make its product as successful as possible in the market. For this, it is necessary that the drug has a therapeutic effect, without causing harm to healthy organisms. To obtain more detailed information about the properties of the active substance, preclinical studies are conducted according to such characteristics as:
- General toxicity. This characteristic determines how harmful the drug is and what is its toxic and lethal dose.
- Reproductive toxicity. This characteristic relates to the reproductive function of the body.
- Teratogenicity. This concept means the level of negative effects on the fetus during pregnancy.
- Allergenicity. The ability of a substance to cause allergies.
- Immunotoxicity This property is very important, since immunity is difficult to recover in case of violations.
- Pharmacokinetics Means the mechanism of movement of matter in the body.
- Pharmacodynamics If the previous paragraph determines the effect of the body on a change in the substance, then pharmacodynamics speaks of how the test substance affects the body.
- Mutagenicity is the ability of a drug to cause mutations.
- Carcinogenicity. This is a rather complicated aspect for studying at the stage of preclinical studies, since the formation of malignant tumors in the body is still poorly studied. But substances, the introduction of which into the body gave a clearly associated reaction of the formation of tumors, do not go through this stage and are rejected.
Researching
The process of conducting preclinical studies of drugs depends largely on what is being studied. So, for example, the development of a new drug is an extremely long and expensive process, since a new drug must go through all stages of testing. While the development of generics should take into account the general toxicity and pharmacokinetics of the drug. Of course, in special cases and for a generic, additional research may be required, however, even despite this, the production of analog drugs is much less expensive both in time and financially.
In preclinical studies, the laboratory also determines the dosage of the drug, which are therapeutic (have a therapeutic effect), the dependence of the level of effect on the size of the dose, as well as lethal and toxic doses of the test substance. All these data should be entered into a detailed report describing all the stages, data and tasks of the tests.
In addition to the results, the report should contain a plan, a guide and a summary of the admission or non-admission of the drug to the next stages of development.
Tasks
The studied substance gets to the stage of preclinical studies with an already defined composition and approximate information about its possible properties, obtained on the basis of the chemical properties of substances close to it in structure. The presenter should determine its properties in more detail, for which she has the following tasks:
- Assessment of the efficacy and effectiveness of the substance under the conditions intended for use.
- The process of administering and delivering a drug to a target in the body. To this end, pharmacokinetics are being studied.
- Safety of the drug: toxicity, mortality, negative impact on the physiological properties of the body.
- How expedient it is to launch the drug on the market, it is better than analogues that are already available in medical practice, and how expensive the production will be.
The latter task is also important, since the process of creating even a generic is extremely costly both in financial and time investments, and in human efforts.
Preclinical studies of drugs do not require a large amount of substance for their conduct, however, in the process of studying it is also necessary to take into account the future need for large-scale mass production. Also, since most large pharmaceutical companies operate according to the GMP standard (Good Manufacturing Practices), a certain batch of the future medicinal product must be produced taking into account the requirements of this standard.
Guidelines for preclinical studies and their management
Since the process of conducting such projects is very complicated, managers should have a wealth of experience both in the managerial and medical fields, as well as in organizing the work of teams of highly qualified specialists engaged in work on different areas of the overall project. In addition, preclinical studies of drugs require special care in the work, as the results directly affect the health of consumers.
For this purpose, organizations conducting preclinical tests create their own instructions and rules. So, the manufacturer of medicines is guided, first of all, by their own documents called SOPs (standard operating procedures), which describe in detail the process of performing a specific action within the development framework.
In addition, there are general standards that govern the entire process of the emergence of a new drug, from the search and development of its formula to production and clinical research. These are GMP standards, European Medicines Agency guidelines and the laws of the country of origin. These standards are used by everyone who conducts safety tests: large pharmaceutical giants, preclinical research centers and laboratories providing independent toxicity examinations.
Also, among the advanced countries for the development of new drugs, a single document was approved to unite and standardize the production formats of drugs: “General technical document”. It was developed and approved by a special International Conference on the harmonization of technical requirements for the registration of pharmaceutical products intended for human use. The list of countries that signed the document includes Japan, the USA and European countries. Thanks to him, pharmaceutical companies are no longer required to submit data on the results of their searches in the field of new drug development to various control and supervision bodies.
Thus, at the moment there is no single guide to conducting preclinical studies, however, work is underway towards combining many scattered regulatory documents into several general documents.
Process
The toxicity research process itself follows a similar algorithm developed over the years of such control. Preclinical studies of the drug always begin with the preparation of a detailed plan and design, after which the laboratory begins to begin the studies themselves. Specialists create computer models that test the effect of the test substance on the body. Using cell cultures, the substance is checked for general toxicity to body cells. With the help of animal studies, therapeutic dosages are determined, as well as specific types of toxicity, allergenicity and carcinogenicity of the substance.
During the control, the statistics obtained in the process are collected and carefully studied, after which the laboratory generates a final report and passes it to the research customer.
results
The results of preclinical studies are presented in the form of a report that indicates whether it is possible to allow the test substance to the next stage of testing - clinical studies. Immediately after the preclinic, the substance should be tested on the organisms of healthy volunteers, so it is extremely important to make sure that it is non-toxic before being tested in humans.
Also, the results of these studies are included in the statistical database of the company, and the information obtained as a result of studies of a specific substance can be supplemented with a library of data on drugs with similar chemical composition. This will contribute to a more accurate search for the next candidate for new medicinal substances.
Admission to clinical trials
The transition of the drug to the stage of clinical trials (in particular, to testing in healthy people - the first stage of clinical trials) is possible only after a proven absence of toxicity, carcinogenicity and other negative effects that appear in and outside organisms of other species.
For the transition of the drug to the final stage of research - research on patients with diseases corresponding to the therapeutic group of the drug - a sufficiently long time must pass. This time is needed to find out the delayed effects of taking a substance that did not appear immediately in preclinical trials and in the first clinical phase.
On average, up to 10 years can elapse between the appearance of a specific active substance as a result of development and the release of a finished product under the brand name to the market. However, this is not all: over the next 10 years, the company actively collects data on efficiency and safety from ordinary consumers of its product. This allows you to improve and develop it, but in some cases, the presence of a large number of side effects can make the company refuse to release the drug.
Cost
The cost of a full cycle of research on a new drug can be in the millions and billions of dollars. Therefore, most innovative drugs are developed by large pharmaceutical holdings, whose turnover is extremely high and allows you to invest in the research and production of new drugs.
Smaller manufacturers of pharmaceutical products prefer to market generic drugs that are simpler and cheaper to develop and research. These are analogues of the original drugs in which the same active substance is located. According to the legislation of most countries, such drugs have the right to undergo a shortened procedure for both clinical and preclinical studies. This greatly reduces the cost of their production.
However, immediately after preclinical studies, the generic must undergo additional tests - bioequivalence tests. Such tests are among those that are carried out at the final stage of preclinical trials, as well as at all stages of the clinical. Most generics produced by large pharmaceutical giants have high bioequivalence, and they can replace the original drugs.