Launching a new pharmaceutical product on the market is a long, complex and multi-stage process. One of the longest stages in the development of a drug is its safety studies. Studies can last up to 10 years and require large budgets for their implementation. One of the first stages of safety studies are preclinical studies, which allow you to determine the overall toxicity of the substance obtained as a result of scientific research.
What is this?
These are, first of all, the security measures taken in the development of a medical product. Also, during the preclinical study, the toxicity and pharmacokinetics (mechanism of movement, distribution and excretion of the drug from the body) of a potential medical product are being 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 research, but also the process of finding the formula of the active substance and creating the correct dosage form for it. That is, preclinical research is an extremely important, but still not the only aspect of preclinical work.
Types of preclinical studies
The process of studying general toxicity follows several paths at once:
- Modeling on the computer. This allows you to make predictions based on information about the chemical structure of the substance and its properties obtained during the search process.
- Laboratory research. They include testing the safety of the future drug in cell cultures. Most people think of preclinical drug trials as tests outside the body. In order to centrally conduct various toxicity tests, pharmaceutical companies and the state organize specialized production facilities. It is the centers of preclinical studies that are the main research structures conducting such tests. But the longest way is, of course, animal testing.
- Toxicity studies in living organisms, ie animals. Plants are also used, and in rare cases, drugs are tested on humans.
To create complex drugs for the treatment of serious human diseases, all the possibilities for preclinical and clinical studies are used. Therefore, the safety check of the substance at the initial stage is done for all three components of the research process.
What aspects of security are being investigated
The manufacturer of both a new drug and a generic drug strives to make its product as successful as possible on the market. To do this, it is necessary that the drug has a therapeutic effect, without causing damage to he althy organisms. To obtain more detailed information about the properties of the active substance, preclinical studies are carried out on 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 concerns the reproductive function of the body.
- Teratogenicity. This concept means the level of negative impact on the fetus during pregnancy.
- Allergenic. The ability of a substance to cause allergies.
- Immunotoxicity. This property is very important, since immunity is difficult to restore in the event of violations.
- Pharmacokinetics. Means the very mechanism of movement of matter in the body.
- Pharmacodynamics. If the previous paragraph defines the influence of the body on the change of the substance, then pharmacodynamics speaks of how the test substance affects the body.
- Mutagenicity - the ability of a drug to cause mutations.
- Carcinogenicity. This is a rather difficult aspect to study at the stage of preclinical studies, since the formation of malignant tumors in the body is still poorly understood. But substances, the introduction of which into the body gave a clearly related reaction of tumor formation, do not pass this stage and are rejected.
Research
The very process of conducting preclinical drug trials 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 the stages of testing. While the development of generics should take into account the overall toxicity and pharmacokinetics of the drug. Of course, in special cases, and for a generic drug, additional research may be required, however, even so, the production of analogue drugs is much less costly, both in time and financially.
In preclinical studies, the laboratory also determines the dosages of the drug that are therapeutic (have a curative effect), the dependence of the level of effect on the size of the dose, as well as the lethal and toxic doses of the test substance. All this data must be entered into a detailed report describing all the stages, data and tasks of the tests carried out.
In addition to the results, the report should contain a plan, guidelines and a summary of the approval or non-admission of the drug to the next stages of development.
Tasks
The substance under study enters the stage of preclinical studies with an already determined composition and approximate information about its possible properties, obtained on the basis of the chemical properties of substances similar in structure to it. The pre-clinic must define its properties in more detail, for which the following tasks are set for it:
- Evaluation of the potency and effectiveness of a substance under the conditions intended for use.
- The process of administering and delivering a drug to a desired target in the body. For this purpose, pharmacokinetics are studied.
- Safety of the drug: toxicity, lethality, negative impact on the physiological properties of the organism.
- How feasible is it to launch a drug on the market, is it better than analogues already available in medical practice, and how expensive will it be to manufacture.
The last task is also important, since the process of creating even a generic is extremely costly both in terms of financial and time investments, and in terms of human effort.
Pre-clinical studies of drugs do not require a large amount of substance to conduct them, but the study process must also take into account the future need for large-scale mass production. Also, since most large pharmaceutical companies work according to the GMP (good manufacturing practice) standard, a certain batch of the future drug must be produced taking into account the requirements of this standard.
Guidelines for preclinical research and management
Since the process of carrying out such projects is very complicated, managers should have a lot of experience both in the managerial and medical fields, and in organizing the work of teams of highly qualified specialists working on different areas of a common project. In addition, preclinical studies of drugs require special care in their work, as the results directly affect the he alth of consumers.
To this end, preclinical testing organizations create their own guidelines and rules. Thus, a drug manufacturer is primarily guided by its own documents called SOPs (standard operating procedures), which describe in detail the process of performing a specific activity within the development.
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, instructions from the European Medicines Agency and the laws of the manufacturing country. Everyone who conducts safety tests uses similar standards: large pharmaceutical giants, preclinical research centers and laboratories that provide independent toxicity reviews.
Also, among the leading countries in the development of new drugs, a single document was approved, designed to unite and standardize production formatspreparations: "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 for Human Use. The list of countries that signed the document included Japan, the United States and European countries. Thanks to it, pharmaceutical companies no longer need to submit data on the results of their research in the field of new drug development to various regulatory authorities.
Thus, there is currently no unified guideline for conducting preclinical studies, but work is underway to combine many disparate regulatory documents into several common documents.
Process
The toxicity study process itself follows a similar algorithm developed over the years of such control. Preclinical studies of a drug always begin with a detailed plan and design, after which the laboratory begins the study itself. Specialists create computer models on which they test the effect of the test substance on the body. Using cell cultures, the substance is tested for general toxicity to body cells. Animal studies determine therapeutic dosages, as well as specific toxicities, allergenicity and carcinogenicity of the substance.
During the control, the statistical data obtained in the process are collected and carefully studied, after which the laboratorygenerates a final report and sends it to the research customer.
Results
The results of preclinical studies are provided 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 preclinical, the substance must be tested in he althy volunteers, so making sure it is non-toxic before it is tested in humans is extremely important.
Also, the results of these studies fall into the company's statistical database, and information obtained as a result of studies of a particular substance can be supplemented by a data library of preparations similar in chemical composition. This will contribute to a more accurate search for the next candidate for new drugs.
Approval of the drug for clinical trials
The transition of a drug to the stage of clinical trials (in particular, to trials on he althy people - the first stage of clinical trials) is possible only after the proven absence of toxicity, carcinogenicity and other negative effects manifested in and outside organisms of other species.
To move a 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 from taking the substance, which did not appear immediately in preclinical trials and at the first stage.clinical.
On average, it can take up to 10 years between the appearance of a specific active substance as a result of development and the release of a finished drug under a trade name on the market. However, that's not all: over the next 10 years, the company is actively collecting data on the effectiveness 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 may force the company to 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 them to invest in the research and production of new drugs.
Smaller pharmaceutical manufacturers prefer to market generic drugs that are simpler and cheaper to develop and research. These are analogues of original medicines containing the same active substance. According to the legislation of most countries, such drugs are eligible to undergo an abbreviated procedure for both clinical and preclinical studies. This makes them much cheaper to produce.
However, immediately after preclinical studies, the generic must pass additional tests - tests for bioequivalence. Such tests are among those performed at the final stage of preclinic altrials, as well as in all stages of clinical. Most generics produced by major pharmaceutical giants have high bioequivalence and can be substituted for original drugs.
