The most complete new drug research and development process

　　In recent years, due to the support of the national policy, the biomedical industry in our country is becoming the most active industry, and medical research and development can be described with each passing day. In view of the continuous updating of the regulatory policy of the FDA, more and more enterprises and personnel are engaged in pharmaceutical research and development. Given the increasing number of new people engaged in pharmaceutical research and development, it is necessary to make a brief review of the basic process of drug research and development.

　　The concept of modern medicine includes peptides, proteins and antibodies, (oligo) nucleotides, small molecule-antibody complexes, and vaccines in addition to our traditional small-molecule compounds (e.g., aspirin, artemisinin). The following is an overview of the basic process of new drug development (mainly 1.1 innovative drugs) from scratch to market, taking traditional small-molecule compound drugs as an example.

Schematic diagram of innovative drug development process

01 DrugDiscovery

　　1. Selection and confirmation of drug action targets and biomarkers

　　In the early stage, people have limited understanding of the target of drug action, often only know the effective, but do not know how to effect. For example, aspirin has been known to have antipyretic, anti-inflammatory, analgesic, antithrombotic and even anti-cancer effects for more than 100 years. It was not until 1971 that John R. Vane, a British scientist, published a paper in the journal Nature stating the Aspirin action mechanism as inhibiting prostaglandin synthesis and was awarded the Nobel Prize in Physiology and Medicine in 1982. The research progress of modern biomedicine and the establishment of human gene map have made the mechanism of disease more accurate and provided clear direction and specific targets for the development of new drugs.

　　2. Determination of leadcompound

　　Once a target has been selected for a drug's action, a medical chemist first has to find a compound that acts on that target. This compound can come from natural products (animals, plants, sea creatures); It can also be a compound designed and synthesized by computer simulation according to the spatial structure of the target. It can also be based on literature reports or previous research findings of other projects. For example, a compound has pharmacological activity or side effect on the target and so on. The erectile dysfunction drug Viagra was developed from its side effects. At present, our common method is to track the drug development of a certain target by foreign research and development institutions, and use their compounds as the lead, hoping to design more excellent compounds.

　　3. Study on structure-activity relationship and screening of active compounds

　　A large number of new compounds were designed and synthesized around the lead compounds. By analyzing the structure-activity relationship between the activity data of the synthesized compounds and the structure of the compounds, the subsequent structural optimization and modification of the compounds were further effectively guided, in order to obtain compounds with better activity.

　　4. The selection of a candidate for a drug

　　Through the structure-activity relationship study, all the optimal compounds that meet the basic biological activity are optimized in several rounds, and are generally selected as drug candidates for development. At this time, the work of pharmaceutical chemists engaged in the discovery of new drugs was temporarily ended.

02 Preclinical research

　　After the candidate drug is determined, new drug development enters the development stage. The goal of the first stage of drug development is to complete preclinical toxicology studies and submit "investigational new drugs" to the authorities of drug administration new drug, IND) application. New drug development requires multidisciplinary collaboration, such as synthesis process chemistry, toxicology, pharmacology, pharmacokinetics, pharmaceutical products, etc. In addition, all specialties need the support of analytical chemistry.

　　1. ChemicalManufacture and Control (CMC)

　　The first step in drug development is the development of API synthesis process (ProcessR & D) It is a process of continuous improvement. The first batch of API to be supplied is mainly for toxicology studies (100-1000g), the requirement is as fast as possible, and cost is not a major consideration. Therefore, as long as the pharmacochemical route can achieve toxicological batch synthesis, the process research and development department will adopt. However, with the advancement of the project, the process department will design a new synthesis route according to the needs, and develop a reasonable production process to meet the needs of phase I -- III clinical drugs and commercialization; Similarly, the pharmaceutical department will first administer the drug in its simplest form, complete toxicological studies, and then continuously complete prescription process studies to develop commercial pharmaceutical processes.

　　2. Pharmacokinetics (PK)

　　Understanding the absorption, distribution, metabolism, and excretion (ADME) of drugs in animals can guide clinical studies on the form of administration (oral, inhalation, injection), frequency and dose.

　　3. SafetyPharmacology

　　To demonstrate the biological activity of the compound against the specific target disease, and to evaluate the effects of the drug beyond efficacy, such as possible side effects, especially on the cardiovascular, respiratory, and central nervous systems.

　　4. Toxicology

　　There are many types of toxicological studies, including acute toxicity, subacute toxicity, chronic toxicity, reproductive toxicity, carcinogenicity, mutagenicity and so on. In order to accelerate the early verification of the efficacy of new drugs, especially for some anti-cancer drugs, some time-consuming and expensive toxicological tests (such as carcinogenicity, reproductive toxicity) may be allowed to be carried out at the clinical trial stage.

　　5. Preparation development

　　Preparation development is an important part of drug development. Early-stage drug studies do not require full prescription development. All studies focus on toxicology studies and convenient administration during Phase I clinical trials, with the goal of bringing drug candidates to the clinic as soon as possible. As the project progressed, more and more research was carried out on delivery methods and prescriptions. For example, some drugs have poor gastrointestinal absorption and need to be developed as injections. Some drugs are inactivated in stomach acid and need to be developed into enteric preparations. Some compounds do not dissolve well, but this problem can also be partially solved by preparations.

　All of this is collectively known as preclinical research, the first stage of drug development. The procedure of each preclinical experiment is not strictly in this order, but 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 the synthesis route, develop a new synthesis process, and provide sufficient quantities of API to meet the needs of the pharmaceutical department for drug research and phase I clinical drug use 9-12 months later.

　　Therefore, whether the project is promoted smoothly depends on whether the coordination and cooperation between the various professions are close.

　　03 Clinicalstudies

　　When a compound has passed a preclinical trial, a New Drug Clinical Investigation Application (IND) is filed with the FDA so that the compound can be tested in humans. The application for clinical study of a new drug requires the submission of materials from previous trials; And a description of where, by whom, and how clinical trials are planned to be conducted; The structure of the new compound; Mode of administration; (a) All toxic conditions found in animal tests; The manufacturing and production of the compound. All clinical protocols must be InstitutionalReview Board, IRB) review and approval must also be submitted annually to the FDA and IRB Report the progress and results of a clinical trial. In the United States, if the FDA does not reject an application within 30 days of its submission, the new drug is considered valid and can be tested in humans. In China, formal approval from the NMPA is required before entering the clinic.

Phase I clinical trial

　　Phase I clinical trials are the first trials in which a new drug is used in humans to study its properties during drug development. In this stage of clinical trials, 20 to 100 normal and healthy volunteers (usually tumor patients for tumor drugs, but fewer) are recruited. Under strictly controlled conditions, drugs of different doses (with the increasing understanding of the safety of new drugs, the dose is gradually increased, and multiple doses can be administered) are tested on healthy volunteers. Hospitalization for close monitoring for 24 hours, where blood concentration, excretory properties and any beneficial or adverse effects of the drug are carefully monitored to evaluate the nature of the drug in the human body. Data on absorption, distribution, metabolism and excretion as well as efficacy duration should also be obtained through clinical trials at this stage. And information on the highest and lowest doses of drugs to determine the appropriate dose for future use in patients. Therefore, the phase I clinical trial is a preliminary clinical pharmacology and human safety evaluation test, which aims to observe the tolerance degree and pharmacokinetics of new drugs, and provide a basis for the formulation of drug administration schedule and safe dose.

05 Phase II clinical trial

　　In order to prove the efficacy of a drug, a clinical study must be conducted on real patients, known as a phase II clinical trial.Phase II trials usually involve 100 to 500 patients. The main objective is to obtain data on the effectiveness of drug therapy.

　　The experimental new drug was given to a limited number of patient volunteers to evaluate its pharmacokinetics and excretion. That's because the drugs work differently in people with the disease than they do in healthy volunteers, especially those that affect the intestines, stomach, liver and kidneys. Phase II clinical trials are generally conducted through randomized blind controlled trials (other design forms can also be adopted according to the specific purpose) to make a preliminary evaluation of the effectiveness and safety of new drugs, and provide a basis for the design of phase III clinical trials and the determination of drug dosage scheme.

06 Phase III clinical trial

　　When a new drug is advanced to phase III clinical, the study of API and preparation process is also advanced to the corresponding stage. Phase III clinical drugs are provided by commercial manufacturing process. Generally speaking, the production process of commercial API should consider the following factors: product quality, production safety, production cost, environmental impact, production stability and sustainability.

　　Phase III clinical trials are usually required 100-500 clinical and inpatient patients, under the strict supervision of the physician, were further provided with information on the effectiveness of the drug and the identification of side effects and interactions with other drugs. This phase of the trial typically involves controlled and double-blind trials (in which neither the doctor nor the patient knows whether they are receiving a new drug, an older drug, or a placebo) with parameters related to the experimental drug and a marketed drug, and an expanded multicenter clinical trial with a larger group of patient volunteers. Finally, based on rigorous statistical data analysis, the effectiveness and tolerability (or safety) of the drug are further evaluated to determine whether the new drug is superior or no worse than the existing "old drug" in the market. Phase III clinical trial is not only the confirmation stage of therapeutic effect, but also the key stage to provide the basis for drug registration application approval. This stage is the busiest and most concentrated part of clinical research project, and undoubtedly the most important step in the whole clinical trial. Phase III clinical studies tend to last several years.

　　In addition to studies in adult patients, safety in older patients, and sometimes in children, is particularly studied. In general, elderly and critically ill patients require lower doses because their bodies cannot effectively clear the drug, making them less tolerant of adverse reactions, and special studies should be conducted to determine the dosage. However, children have the characteristics of mutation sensitivity, late toxicity and different pharmacokinetic properties, so the balance between efficacy and adverse drug reactions should be a special concern when deciding the use of drugs in children. In foreign countries, clinical trials involving children usually start after the phase III of adult trials. If a disease occurs primarily in children and is severe and no other treatment is available, the FDA allows Phase I clinical trials to begin directly in children, that is, to begin pharmacological evaluation in children if no adult data is available. There are no clear rules about this in our country.

　　A bad response from any of these steps could kill a drug candidate. Perhaps the most tragic outcome was that the project was simply canceled.

　　Fewer new drugs are making it to market through full Phase 3 clinical reviews, in part because it is getting harder to develop new drugs that have a better comprehensive evaluation than those already on the market. Taking a drug from source to phase 3 is an expensive process. Published data suggest that, on average, a new drug costs about $1billion US Dollars). Because drug development is so expensive, big companies can't afford to run multiple research projects simultaneously, and small companies can't afford to go through the entire process. One trend in drug development is that smaller companies are better able to identify gaps in the market and develop drug candidates that perform well in preclinical studies. The larger company buys the project to continue development, either by acquiring a smaller company or by buying patents (or rights). In the case of a patent purchase, the small company is paid a "bonus", called a milestone, based on the final stage of the project.

New Drug Application (NDA)

　　After all three phases of clinical trials have been completed and all data and data analyzed, the safety and efficacy of the drug have been demonstrated and the holder of the new drug may submit a new drug application to the regulatory authority (C)FDA. A new drug application requires all the scientific data collected. Typically, a new drug application can be as large as 100,000 documents Pages and even more! By law, the FDA is supposed to review new drug applications within six months. However, because most of the application materials are too much and there are many irregularities, it is often impossible to complete in such a short time. The China Food and Drug Administration is also trying to improve its work, hoping to shorten the approval time.

08 Approval of Listing

　　Once the new drug application is approved by the drug administration, the new drug can be officially marketed for doctors and patients to choose from. But new drug owners must also regularly submit relevant data to the drug authorities, including the drug's side effects and quality control records. For some drugs, the FDA will require Phase 4 clinical trials to look at long-term side effects.

　　If we can get this far, we can say that we are done for the time being. Very few drugs have made it this far from an initial candidate compound. But approval doesn't mean the drug is safe. Because there's a second 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 continuously. According to the results of monitoring at this stage, the drug specification should be revised. Some of the other things that will be involved in this stage of research are the study of drug compatibility and drug use contraindications. If an approved drug is found to have a serious adverse effect not seen in previous studies, such as a significant increase in cardiovascular disease in the population, the drug can also be forced to carry a warning or even be taken off the market. Such as Merck's anti-arthritis drug Vioxx It "voluntarily" withdrew from the market in 2004 due to increased risk of cardiovascular disease.

　　In short, drug development is a high risk, high investment, and of course high return industry. The research and development period is long, involving the close cooperation and coordination of multiple disciplines and professions. If the professional functional departments of a new drug research and development institution are properly matched, the professional staff can do their own work well, and pay attention to the cooperation among the majors and timely communication with the FDA, the management of new drug research and development is not complicated, as long as there is a responsible project manager, according to the agreed key time nodes of the project timely coordination of the work of all functional departments, The project can proceed as planned.