In recent years, due to the support of national policies, China's biomedical industry is becoming the most active industry, and the development of pharmaceutical research and development is changing with each passing day. In view of the constant updating of regulatory policies of the drug regulatory bureau, more and more enterprises and personnel engaged in pharmaceutical research and development are engaged. In view of the increase of new personnel engaged in pharmaceutical research and development, it is necessary to make a simple review of the basic process of new drug research and development.
In addition to our traditional small molecule compounds (such as aspirin and artemisinin), the concept of modern medicine also includes polypeptides, proteins and antibodies, (oligonucleotides), small molecule antibody complexes, and vaccines. Take the traditional small molecule compound medicine as an example to give an overview of the basic process from scratch to the final market of new drugs (mainly class 1.1 innovative drugs).
1. Selection and confirmation of drug target and biomarker
In the early days, people had limited understanding of the target of drug action, and often only knew how to work, but did not know how to work. For example, for one hundred years, aspirin has been known to have antipyretic, antiphlogistic, analgesic, antithrombotic and even anticancer effects. It was not until 1971 that John R. van, a British man, published in the journal Nature that he clarified that the mechanism of aspirin action was to inhibit prostaglandin synthesis, and won the Nobel Prize in physiology and medicine in 1982. With the development of modern biomedical research and the establishment of human gene map, people can understand the mechanism of disease more accurately, which provides a clear direction and specific target for the development of new drugs.
2. Determination of lead compound
Once the target of drug action has been selected, medical chemist should first find a compound that has effect on the target. This compound can come from natural products (animals, plants, marine organisms); it can also be a compound designed and synthesized by computer simulation according to the spatial structure of the target; it can also be found according to literature reports or other previous research projects. For example, a certain class of compounds has pharmacological activities or side effects on the target and so on. Viagra, a drug for erectile dysfunction, has been developed for its side effects. At present, our common method is to track the drug development of a target by foreign research and development institutions, and take their compounds as the lead, hoping to design better compounds.
3. Study of structure-activity relationship and screening of active compounds
Around the lead compounds, a large number of new compounds were designed and synthesized. Through the analysis of the structure-activity relationship between the activity data of the synthesized compounds and the structure of the compounds, we can further effectively guide the subsequent optimization and modification of the structure of the compounds, in order to get the compounds with better activity.
4. Selection of candidate drugs
Through the study of structure-activity relationship, all the selected compounds satisfying the basic biological activity are optimized in several rounds, and generally selected as candidate drugs for development. At this time, the work of pharmaceutical chemists engaged in the discovery of new drugs is temporarily over.
Pre clinical toxicology studies
After the candidate drugs are determined, the development of new drugs will enter the development stage. The goal of the first stage of drug development is to complete the pre clinical toxicology research and submit the application for "investigational new drug (ind)" to the drug regulatory department. New drug development requires multidisciplinary collaboration, such as process chemistry, toxicology, pharmacology, pharmacokinetics, preparations, and other disciplines. In addition, all disciplines need the support of analytical chemistry.
1. Chemical manufacturing and control (CMC)
The first step of new drug development is process R & D, which is a process of continuous improvement and improvement. The first batch of APIs is mainly used for toxicology research (100-1000g). The requirement is that the faster the better, and the cost is not the main consideration. Therefore, as long as the pharmaceutical route can realize the toxicological batch synthesis, the process research and development department will adopt it. However, with the promotion of the project, the process department will design a new synthesis route according to the needs, develop a reasonable production process to meet the needs of phase I-III clinical medication and commercialization; similarly, the preparation department will first give drugs in the simplest form, complete the toxicology research, and then continue to complete the prescription process research, and develop a commercialized preparation process.
2. Pharmacokinetics (PK)
To understand the absorption, distribution, metabolism and excretion (ADME) of drugs in animals, these data can guide clinical research on the form of Drug Administration (oral, inhalation, injection), the frequency and dose of drug administration.
3. Safety pharmacology
It is proved that the compound has biological activity for specific target diseases, and it also evaluates the effect of the drug on other than curative effect, such as possible side effects, especially on cardiovascular, respiratory and central nervous system.
There are many kinds of toxicological studies, including acute toxicity, subacute toxicity, chronic toxicity, reproductive toxicity, carcinogenicity, mutagenicity, etc. In order to accelerate the effectiveness of new drugs, especially for some anticancer drugs, some time-consuming and expensive toxicological experiments (such as carcinogenicity and reproductive toxicity) can be allowed to be carried out in clinical trials.
5. Preparation development
Preparation development is an important part of drug research and development. Early preparation research does not need complete prescription development. All researches focus on toxicology research and convenient administration in phase I clinical. The purpose is to promote candidate drugs to clinical as soon as possible. With the development of the project, the research on drug administration and prescription is more and more comprehensive. For example, some drugs with poor gastrointestinal absorption need to be developed for injection. Some drugs lose their activity in gastric acid, so they need to be developed into enteric preparations. Some compounds have poor solubility, which can also be partially solved by preparations.
All of the above are collectively referred to as preclinical research, which is the first stage of drug development. The steps of preclinical experiments are not carried out in strict accordance with the above order, but in a mutually inclusive and coordinated relationship. For example, the API process R & D department, after completing the synthesis of toxicological batch samples, must immediately carry out the selection of synthesis routes, develop new synthesis processes, and provide sufficient APIs to meet the needs of the preparation department for the preparation research of APIs and phase I clinical medication after 9-12 months.
Therefore, the smooth progress of the project depends on the close coordination and cooperation between the disciplines.
After a compound has passed the preclinical test, it is necessary to submit a new drug clinical research application (ind) to the FDA, so that the compound can be used in human trials. The clinical research application of new drugs needs to provide the materials of previous trials; and the description of where, who and how to carry out the clinical trials; the structure of the new compound; the way of administration; all toxicity conditions found in the animal trials; the manufacturing and production conditions of the compound. All clinical protocols must be reviewed and approved by the institutional review board (IRB), and the progress and results of clinical trials must be reported to FDA and IRB once a year. In the United States, if the FDA does not reject the application within 30 days after the application is submitted, the application for clinical research of the new drug will be regarded as valid and can be tested in human body. In China, CFDA approval is required before entering clinical practice.
Phase I clinical trial
In the process of new drug development, the first trial of new drugs used in human body to study the properties of new drugs is called phase I clinical trial. In this stage of clinical trials, 20-100 normal and healthy volunteers (usually tumor patients for tumor drugs, but less) are generally required to be recruited. Under strict control, different doses of drugs (with the increase of understanding of the safety of new drugs, the dose of drugs is gradually increased, and can be administered in multiple doses) are given to healthy volunteers and hospitalized In order to carry out 24-hour close monitoring, carefully monitor the blood concentration, excretion nature and any beneficial reaction or adverse effect of the drug, so as to evaluate the nature of the drug in the human body. At the same time, the data and data of absorption, distribution, metabolism and excretion as well as the duration of efficacy, as well as the information of the highest and lowest dose of the drug should be obtained through the clinical trials at this stage, so as to determine the appropriate dose to be used in patients in the future. It can be seen that phase I clinical trial is a preliminary clinical pharmacology and human safety evaluation test, which aims to observe the tolerance degree and pharmacokinetics of human body to new drugs, and provide basis for formulation of drug delivery scheme and safe dose.
Phase II clinical trial
In order to confirm the therapeutic effect of drugs, it is necessary to carry out clinical research on real patients, i.e. phase II clinical trial. Phase II clinical trials usually involve 100-500 patients. Its main purpose is to obtain the data of the effectiveness of drug treatment.
The experimental drug was given to a certain number of patients and volunteers to evaluate the pharmacokinetics and excretion of the drug. That's because drugs work differently in people who are sick than in healthy volunteers, especially those that affect the intestines, stomach, liver, and kidneys. In phase II clinical trials, the effectiveness and safety of new drugs are preliminarily evaluated by randomized blind controlled trials (other design forms may be adopted according to specific purposes), which provide basis for the design of phase III clinical trials and the determination of dosage scheme.
Phase III clinical trial
When a new drug is advanced to phase III clinical, the research of API and preparation technology is also advanced to the corresponding stage. The third phase clinical medication is provided by commercial production process. Generally speaking, the following factors should be considered in the production process of BPC: product quality, production safety, production cost, environmental impact, production stability and sustainability.
Phase III clinical trials usually require 1000-5000 clinical and inpatient patients. Under the strict supervision of doctors, further information on the effectiveness of the drug, identification of side effects, and interaction with other drugs can be obtained. In this phase of trial, the relevant parameters of the trial drug and placebo (excluding active substances) or the marketed drug are generally controlled and double-blind trial (doctors and patients do not know that they are taking new drugs, old drugs or placebo), and the expanded multi center clinical trial is carried out in a wider range of patient volunteers. Finally, according to the strict statistical data analysis, further evaluate the effectiveness and tolerance (or safety) of the drug, determine whether the new drug is superior to (superior) or not inferior to (not inferior) the existing "old drugs" in the market. Phase III clinical trial is the confirmation stage of therapeutic effect and the key stage to provide basis for drug registration and approval. It is the busiest and most concentrated part of clinical research project, and undoubtedly the most important step in the whole clinical trial. Three phase clinical studies often last for several years.
In addition to the study of adult patients, we should also study the safety of drugs for elderly patients, sometimes including children. Generally speaking, the dosage required by elderly patients and critical patients is lower, because their bodies can not effectively remove the drugs, making their tolerance to adverse reactions worse, so special research should be carried out to determine the dosage. However, children have the characteristics of mutation sensitivity, delayed toxicity and different pharmacokinetic properties, so it should be paid special attention to balance the efficacy and adverse drug reactions when deciding the application of drugs in children. In foreign countries, children's clinical trials usually begin after the third phase of adult trials. If a disease mainly occurs in children, and it is very serious and there is no other treatment method, FDA allows phase I clinical trials to really start from children, that is, in the absence of adult data reference, it allows pharmacological evaluation from children. There is no clear stipulation about it in our country.
If the feedback from any of the above steps is not good, it may lead to the death of a candidate drug. The most tragic result may be that the project was cancelled directly. In 2007, Merck had four phase III clinical drug failures.
There are fewer and fewer new drugs that can be listed through all three phases of clinical evaluation, in part because it is more and more difficult to develop new drugs that are better than the comprehensive evaluation of existing drugs on the market. And a drug from the source of research and development to phase 3 clinical is a costly process. Public data show that on average, a new drug costs about one billion US dollars. Because of the huge cost of drug research and development, large companies can not afford to spend so much money to carry out multiple projects at the same time, and small companies do not have so much money to complete the whole process of drug research and development. Now, a trend of drug research and development is that small companies can better identify market vacancies and develop candidate drugs with good performance in pre clinical research stage. At this time, large companies buy small companies or patents (or use rights) to continue to develop the project. In case of patent purchase, a "bonus" will be paid to the small company after the completion of the project according to the final stage of the project, which is called milestone.
New drug application (NDA)
After completing all three phases of clinical trials and analyzing all data and data, the safety and effectiveness of the drug has been proved, and the new drug holder can submit a new drug application to the FDA. New drug applications need to provide all the scientific information collected. Usually a new drug application materials can be up to 100000 pages, or even more! According to the regulations, FDA should review and evaluate the new drug application within 6 months. However, because most of the application materials are too many, and there are many non-standard, it is often not completed in such a short time. China food and drug administration is also trying to improve its work, hoping to shorten the approval time.
Approval for listing
Once the new drug application is approved by the drug regulatory department, the new drug can be officially marketed for doctors and patients to choose. However, the new drug holder must also regularly submit relevant information to the drug regulatory department, including the side effects and quality management records of the drug. For some drug and drug administration departments, the fourth phase clinical trial will be required to observe the long-term side effects.
If we can get to this point, we can say that we have achieved success for the time being. Few drugs have gone from the initial candidate compound to this step. But approval doesn't mean the drug is safe. Because there's another step.
Phase IV clinical study (post marketing monitoring)
After the drug is used in a wide range of people, its efficacy and adverse reactions need to be monitored. According to the monitoring results of this stage, the drug regulatory department requests to revise the drug use manual. This stage of the study will also involve some content, drug compatibility research, drug use taboo. If a drug approved for marketing is found to have serious adverse reactions not found in previous studies at this stage, such as significantly increasing the incidence of cardiovascular disease in the population taking the drug, the drug will also be forced by the regulatory authorities to add warning notes, or even be removed from the shelves. For example, Merck's anti arthritis drug Vioxx was "actively" withdrawn from the market in 2004 due to its increased risk of cardiovascular disease.
In short, new drug research and development is a high-risk, high investment, and of course, high return industry. The R & D cycle is long, involving close cooperation and coordination of multi-disciplinary and multi-disciplinary. If a new drug R & D institution has a reasonable set of professional functional departments, each professional can do their own work well, and pay attention to the cooperation between each professional and the timely communication with the drug administration, the new drug R & D management is not complicated, as long as there is a responsible project manager, according to the agreed key time nodes of the project, to coordinate the work of each functional department in a timely manner, the project will It can be carried out orderly according to the plan.