What is a new drug? Briefly describe the steps of new drug research and development.

It takes an average of 12 years from the initial laboratory research to the final sale in the medicine cabinet. Of the 5,000 compounds in pre-clinical trials, only 5 can enter the follow-up clinical trials, of which only 1 can get the final marketing approval.

Generally speaking, the research and development of new drugs is divided into two stages: research and development. These two stages occur one after another and are interrelated. The mark that distinguishes the two stages is the determination of candidate drugs, that is, the research stage is before the determination of candidate drugs, and the development stage is after the determination. The so-called candidate drugs refer to the active compounds that are about to undergo systematic preclinical trials and enter clinical research.

The research stage includes four important links: determining the target, establishing the model, discovering the lead compounds and optimizing the lead compounds.

First, set goals.

Determining the target of disease and the link and object of treatment is the starting point of creating new drugs and the basis of various operations in the future. Drug targets include enzymes, receptors and ion channels. The proportion of drugs acting on different targets in all drugs is different. Taking 2000 as an example, among the total drug sales in the world, enzyme inhibitors accounted for 32.4%, transporter inhibitors accounted for 16.0%, receptor agonists accounted for 9. 1%, receptor antagonists accounted for 10.7%, and drugs acting on ion channels accounted for 9. 1%. At present, there are two relatively new technologies to confirm the target. One is to establish a transgenic animal model or knock out genes by using gene recombination technology to verify the targets related to specific metabolic pathways or phenotypes. The disadvantage of this technology is that it can't completely eliminate other effects brought by knockout (such as phenotypic changes caused by the start of compensation mechanism). ). The second is to use antisense oligonucleotide technology to inhibit the translation of specific messenger RNA into protein, so as to identify new targets. For example, embedding small nuclear ribonucleic acid (snRNA) to control gene expression plays an important role in confirming the target.

Second, the establishment of model

After selecting the target, a biological model should be established to screen and evaluate the activity of the compound. Screening criteria are usually formulated, and if the compound meets these criteria, the research project will continue; If it does not meet the standards, the study should be terminated as soon as possible. Generally speaking, the criteria for testing the model are: the in vitro activity strength of the compound; Whether the animal model can reflect the corresponding disease state of human body; Dose (concentration)-effect relationship of drugs, and so on. Quantitative and repeatable in vitro model is the premise of evaluating the activity of compounds. In recent years, in order to avoid the late risk of drug development, pharmacokinetic model evaluation (ADME evaluation) and drug stability test are generally carried out at the same time.

Third, the discovery of lead compounds.

The third step of new drug development is to find lead compounds. The so-called lead compounds, also known as new chemical entities (NCE), refer to compounds with certain biological or pharmacological activities obtained through various ways and methods. Because the current knowledge is not deep enough to use enough receptor mechanism to guide drug design, so that drug synthesis does not need to use known models in advance, the discovery of lead compounds depends on the receptors and models determined in the above two steps on the one hand, and becomes a key step in the whole drug research and development on the other. Generally speaking, lead compounds mainly come from the following aspects: the excavation of natural active substances, the improvement of existing adverse drug reactions, and the screening of drug synthesis intermediates. At present, there are two main ways to obtain new lead compounds. First, extensive screening, this unfounded method is actually more effective in actual operation. In the past half century, for this reason, the discovery of lead compounds is very random. For example, this part separated from coal tar was found to have antibacterial effect and was developed into a series of antibiotics such as sallow; Another example is the screening of dye intermediates. It was found that aniline and acetanilide had antipyretic and analgesic effects, and phenacetin and acetaminophen were obtained by transformation. In the past twenty years, computer pre-screening has been used in this process, which has greatly accelerated the research process. In addition, the rational design of lead compounds has also become a research hotspot in this field in recent years. The so-called rational design refers to the targeted design of lead compounds according to known receptors (or receptor unknown but with a series of ligand structure-activity relationship data). This method is different from the general screening, and has a strong purpose, which is conducive to the further development of various structure-activity relationship theories, so it has a very broad prospect.

Fourthly, the optimization of lead compounds

Because the found lead compounds may have defects such as low action intensity or specificity, inappropriate pharmacokinetic properties, strong toxic and side effects or unstable chemistry or metabolism, they can not be directly used as drugs. Therefore, it is necessary to optimize the lead compounds to determine the candidate drugs, which is the last step of new drug research. In short, the optimization of precursor compounds is to prepare a series of compounds according to the similarity principle, evaluate their comprehensive structure-activity relationship and optimize their physical, chemical and biochemical properties. After optimization, the in vitro and in vivo activities were evaluated, and excellent compound-drug candidates were finally obtained through circular feedback.

Pre-clinical and clinical research on verb (abbreviation of verb)

The research and development stages of new drugs are as follows: preclinical trials: laboratory and animal studies conducted by pharmaceutical companies to observe the biological activity of compounds against target diseases and evaluate the safety of compounds. These experiments will take about 3.5 years. New research application (IND): After the pre-clinical trial is completed, the company must submit IND to FDA before it can start human trials of drugs. If the FDA does not issue a statement of disapproval within 30 days, this IND is valid. The proposed IND should include the following contents: preliminary test results, the way, place and object of follow-up research; Chemical structure of the compound; Mechanism of action in vivo; Any toxic and side effects found in animal research and compound production. In addition, IND must be reviewed and approved by the Institutional Review Board. At the same time, follow-up clinical research needs to submit a progress report to FDA at least once a year and get permission.

Clinical trial, phase I: this phase will take about 1 year, and 20 ~ 80 normal healthy volunteers will participate. These tests studied the safety of drugs, including the safe dose range. At this stage, the study also determined the absorption, distribution, metabolism and excretion of drugs in the body, as well as the duration of drug action.

Clinical trial, phase II: At this stage, about 100 to 300 volunteer patients need to participate in some controlled studies to evaluate the efficacy of drugs. This stage will take about 2 years.

Clinical study, Phase III: This phase lasts about 3 years and usually requires 1000 ~ 300 patients from clinics and hospitals to participate. Doctors monitor patients to determine the efficacy and adverse reactions.

NDA): After three stages of clinical trials, the company will analyze all the experimental data. If the data can successfully prove the safety and effectiveness of the drug, the company will apply to the FDA for a new drug. The application for new drugs must include all relevant scientific information held by the company. A typical new drug application has more than 654.38 million pages or more. According to the law, the time limit for FDA to review NDA should be 6 months. But in almost all cases, the process from the first submission to the final approval of FDA exceeded this time limit; 1992, the average review time for new drug applications of new molecular entities is 29.9 months.

Approval: Once the FDA approves the application for a new drug, the new drug can be used by doctors for prescription. The company must continue to submit regular reports to the FDA, including all adverse reaction reports and some quality control records. The FDA may also conduct further research on certain drug requirements (phase IV) to evaluate the long-term efficacy of drugs.

Inventing and researching safe and effective new drugs is a long, difficult and expensive process. This year, research pharmaceutical companies will invest $654.38+026 billion in research and development, doubling every five years.