A must-read for R&D personnel: Sorting out the whole process of innovative drug R&D

Innovative drugs Innovative drugs refer to drugs with independent intellectual property rights
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Compared with generic drugs, innovative drugs emphasize novel chemical structures or new therapeutic uses, which have not been reported in previous research literature or patents
.
With the gradual improvement of China's intellectual property status, the research of innovative drugs will bring high benefits to enterprises, but while obtaining high benefits, it must also bear a corresponding degree of risk
.
It takes 8-10 years from the initiation of a new drug project to the final launch.
Pharmaceutical research on new drugs has gone through a process from discovery to recognition to confirmation.
During this process, safety and effectiveness are always the key to screening and eliminating candidate drugs.
"Absolute Standard"
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In addition to strong financial and technical support, an innovative drug needs to spend a lot of time from research and development to listing.
If there is a problem in any link during this period, all efforts may be in vain, so many companies undertake Can not afford such a risk and prefer to do generic drugs
.
So what is the R&D process of innovative drug R&D? Let's take a look at a rough schematic diagram of the development process
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After reading the schematic diagram of the research and development process above, I believe that everyone has a general understanding of the process of new drug research and development.
Let's analyze each process in depth
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Drug discovery research In other words, it may be better to understand a little bit, that is, what are the main ways of drug discovery? In fact, there are nine ways.
Here we only make a brief statement and do not discuss too much.

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The main approaches of new drug discovery are as follows: Random discovery (accidental discovery), such as: penicillin, propranolol; Obtained from active ingredients of natural compounds, such as: artemisinin, paclitaxel; Existing breakthrough drugs as lead; The endogenous active substances in the body are used as lead compounds; from drug metabolites; from drug synthesis intermediates, (the intermediates have structural similarities with the target compounds, and can also become lead compounds after screening); old drugs and new Application: Many drugs show unexpected effects on certain diseases during clinical application, thus discovering new indications; Combinatorial chemistry and high-throughput screening; Design based on the structure of biological macromolecules
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Here is one thing we must be clear: you can first discover the drug and then determine the target of the drug, or you can first determine the target of the drug, and then find a compound that has an effect on the target
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This compound can be a natural product, or it can be designed by computer simulation according to the spatial structure of the target and then synthesized, or it can be based on previous research findings or literature reports in other projects
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When the drug and the drug's action target are determined, we come to preclinical research
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The goal of the first stage of new drug development is to complete preclinical toxicology research, which requires R&D workers to provide the first batch of APIs as quickly as possible
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At this time, we should pay attention: if the API is a synthetic small molecule or biological macromolecule, then the process route for the synthesis of the API is not a one-step process.
In the earliest stage, as long as the drug chemical route of the API can meet the requirements of the toxicological batch process R&D department can use it
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With the advancement of the project, the process research and development department will design a more perfect synthesis route to meet the needs of Phase I-III clinical drug use and commercialization
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In the same way, the preparation department will first complete the toxicology study in the simplest form of administration, and then continue to optimize the prescription process design to push the project to clinical phase I as soon as possible.

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(During this period, a large number of preparations and analytical experiments need to be done to screen out reasonable prescriptions and processes.
This research process is uncertain and is a gradual process.
) During this period, pharmacokinetics and safety of drugs are also required.
Sexual pharmacology and toxicology research
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The preceding contents are collectively referred to as preclinical research, which is the first stage of drug development
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Each preclinical experiment is a mutually inclusive and coordinated relationship rather than strictly following the above sequence
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When the above work is completed, it will come to clinical research
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When a drug has passed preclinical experiments, the company needs to submit a new drug clinical trial application (IND) to the Food and Drug Administration (C) FDA so that the drug can be used in human experiments
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The application for new drug clinical trials (IND) is actually a very cumbersome process, which requires a lot of preparation work.
Below we summarize the following process based on the application experience of teachers for everyone to understand
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Application process of new drug clinical trial (IND): 1.
Drug development starts from drug discovery and screening.
R&D workers have carried out a series of preliminary work such as synthesis process, preparation process, quality research, etc.
, and also need to carry out a series of preliminary proofs.
, before applying for clinical trials
.
2 Pre-IND meeting To declare an IND to the FDA, first of all, the company needs to have an office in the US or find a suitable US agent to be responsible for communication with the FDA
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FDA has established a variety of mechanisms to effectively communicate with enterprises, such as various formal meetings with enterprises, such as Pre-IND meetings, meetings after the end of Phase II clinical trials, mainly for suggestions on drug development and clarifying FDA requirements , reduce the possibility of detours and the wrong way, and improve the success rate of declaration
.
Before applying for an IND, an enterprise should prepare a Pre-IND to inform the FDA in advance of the basic information of the drug, preliminary research plan, etc.
, usually including the research status of the drug, preliminary research plan, preclinical toxicology and pharmacology, CMC, and clinical trial protocol outline.
overview of
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The most important content is what the company intends to discuss with the FDA at the Pre-IND meeting
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What kind of questions are prepared to ask is actually the most important part of the entire Pre-IND stage
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Generally speaking, companies need to submit a meeting request to the FDA about 60 days before the planned meeting with the FDA
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After the FDA receives the meeting request, it usually arranges the meeting in about 14 days
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Pre-IND briefing materials are generally submitted about 4 weeks before the meeting)
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FDA usually responds to preliminary comments on issues to be discussed, and companies can learn about FDA’s preliminary views on issues.
Under normal circumstances, companies usually only have one opportunity to open a Pre-IND with FDA.
The importance of this meeting can be imagined
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How to ask questions correctly based on the current status of drug research and development and development plans, how to conduct strong negotiations with FDA, and how to maximize benefits for enterprises and obtain valuable FDA guidance are important criteria for testing the professionalism of the registration team
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Generally a few working days after the Pre-IND is over, FDA will provide the official Pre-IND meeting minutes, records and the applicant's discussion results and comments on the issue
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Applicants can also provide their own meeting minutes to FDA after the meeting to express their understanding of the discussion, so as to avoid errors in understanding between the two parties and cause unnecessary trouble
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3 IND application document package According to the results of the discussion between the Pre-IND meeting and the FDA, the applicant prepares the IND application document package
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4 IND review The review work begins when FDA receives the IND application package, and FDA should complete the review within 30 days
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The review results generally include three situations: permission to start clinical, partial clinical restrictions and clinical restrictions
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1 Phase I Clinical Trial Phase I clinical trial is the first time a drug is applied to the human body.
Its main purpose is to study the tolerance of the human body to the drug, and to understand the absorption, distribution, The rule of elimination can provide data support for the formulation of dosing regimens for further experimental research
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Subjects are generally healthy volunteers, and patients may also be selected as subjects under special circumstances
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The general number of test cases is 20-30 cases
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2 Phase II clinical trials This phase of clinical research focuses on the safety and efficacy of the drug
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Placebo can be used as a control drug to evaluate the efficacy of new drugs, and during this process, the influence of the occurrence and development of the disease on the efficacy of the drug can be studied; the dosage and schedule of phase III clinical trials can be determined; more drug safety can be obtained aspect information
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The subjects of this experiment are patients, and the number of test cases is ≥100
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3 Phase III clinical trial This phase of the trial increases the patient's exposure to the investigational drug
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On the one hand, it is necessary to increase the number of subjects, and on the other hand, it is necessary to increase the time for subjects to take medication; determine the ideal dosage regimen for different patient populations, and further verify the effectiveness and safety of the drug
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The subjects of this experiment are patients, and the number of subjects is ≥300
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After the drug enters the phase III clinical trial, the production process of all materials, APIs and preparations used in the production has been basically completely determined, and will not be changed under normal circumstances
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If it is compared with the clinical samples of Phase I/II, such as dosage form, prescription, process, specifications, etc.
, have changed, this is a major change that may affect the quality characteristics of the product, the specific content of the change, the reason for the change should be explained, and attention should be paid to the risk assessment , and conduct appropriate in vitro and in vivo bridging studies on samples before and after the change, depending on the degree of risk
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4 Phase IV clinical trials Phase IV clinical trials are to strengthen monitoring during the practical application of new drugs after they are marketed, and continue to investigate the efficacy and adverse reactions in wider and longer-term practical applications
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Various forms of clinical application and research may be employed
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Phase IV clinical trials should be conducted in multiple hospitals, and the number of observation cases is usually no less than 2,000
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In this phase of the trial, attention should be paid to the investigation of adverse reactions, contraindications, long-term efficacy and precautions in use, so as to detect possible long-term side effects in time and evaluate the long-term efficacy
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In addition, the impact on the patient's economy and quality of life should be further investigated
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After the innovative drug completes the three pre-clinical studies, the researchers analyze all the data and data, and the safety and effectiveness of the drug have been proved, and the company can submit a new drug application to the drug regulatory department (C) FDA
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The approval of a new drug for marketing is not the end of the study, but just another beginning.
It has already been said that the research after the drug is launched is a clinical phase IV study.
At this stage, its efficacy and adverse reactions need to continue to be tested.
Phase I test results to revise the instructions for use of the drug
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This stage also needs to study the compatibility and use of drugs and the contraindications of drug use
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If an approved drug is found to have serious adverse reactions at this stage, the drug is also at risk of being removed from the market
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During this period, the new drug holder must also regularly submit relevant information, including the side effects of the drug and quality management records
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In short, new drug research and development is a high-risk, high-investment, and high-reward industry
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The research and development cycle of new drugs is long, which requires close cooperation and coordination of multiple disciplines and disciplines.

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In recent years, China has attached great importance to pharmaceutical innovation.
Planning guidelines such as "National Innovation-driven Development Strategy Outline", "13th Five-Year Plan for National Science and Technology Innovation", "Pharmaceutical Industry Development Planning Guide" and other planning guides have put forward goals related to the development of innovative drugs, and established A special fund has been established to promote the research and development of new drugs
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Since 2015, the policy environment for innovative drugs has been continuously optimized, and innovation vitality has been continuously released
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In this context, it is of great significance for corporate investment planning and regulatory agencies to encourage innovation
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Finally, I wish China's new drug research and development industry, like the great Chinese nation, to rise rapidly and flourish
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References: [1] Wang Jianying.
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Drug Application and Regulatory Management [M].
China Pharmaceutical Science and Technology Press, 2005.
[2] Zhou Xia, Jin Xin, Chen Jian, et al.
Exploring the application process for clinical trials of new chemical drugs in my country[M].
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China Prescription Drugs, 2021, 19(10):3.
[3] He Xiang, Sun Wei.
Analysis of new drug development and drug registration process [J].
Private Science and Technology, 2010(7):1.