The research and development of new drugs is a systematic project that encompasses the joint efforts of multiple disciplines, the collaboration of multiple departments, and the completion of the “dream”. However, due to the high-risk characteristics of the R&D process, even if everything is devoted to each link, it may not be able to bear fruit in the end. Here, if the establishment of a project is likened to “seed”, then the IND process is like “flowering” and the NDA process is like “result”. At the beginning of the project, tens of millions of seeds were planted, and the ones that can eventually grow fruit are absolutely rare. In real work, if the IND can really grow to the flowering stage, it is already super admired and envied. Because, in this process, most of the R&D personnel in the deep project have done their best and have been favored by the goddess of luck.
IND, Investigational New Drug, generally refers to a new drug that has not been approved for marketing and is undergoing clinical trials at various stages. In actual applications, IND or CTA (clinical trial application) has become synonymous with pre-marketing human clinical trials. The IND application may be one or a sequential group of studies, with the purpose of obtaining evidence of product safety and effectiveness. Generally speaking, INDs can be divided into commercial INDs and non-commercial INDs. Commercial INDs are for registration purposes and can distinguish phase I clinical trials, phase II clinical trials and phase III clinical trials, or exploratory clinical trials and confirmatory clinical trials. . Commercial INDs are usually initiated by drug R&D applicants. Non-commercial INDs are usually not for registration purposes. They are mostly initiated by researchers. It is difficult to define whether they should be classified as exploratory clinical trials or confirmatory clinical trials.
Innovative drugs go through a systematic purgatory process full of thorns from structural design, discovery, and finally approval to market. Briefly, the first is the discovery of the new chemical entity NCE, which mainly includes the identification of lead compounds and candidate drugs; after that, it enters the pre-clinical research stage, which mainly includes pharmacology, toxicology, pharmacokinetics, pre-prescription research, etc. After completing the preliminary pre-clinical evaluation and about to enter the clinical research, the development company applicant must apply for registration to the corresponding drug review department. This node is the content of this article~IND application; the pending drug review department passes the IND application or When there is no feedback, the project enters the next phase, namely phase I, II, and III clinical research; after the pre-clinical research and clinical research are completed or partly completed, if the expected purpose is achieved, the new drug marketing application NDA can be submitted. In order to be approved for marketing; after the listing, the development company still needs to conduct phase IV clinical research and post-marketing monitoring of the product, so that it can fully understand the mechanism, scope, therapeutic effect, side effects, etc. of the drug… .
As mentioned above, before a development company submits an IND application, it needs to conduct a series of preclinical studies on the drug, so as to pave the way for strong safety and effectiveness data for clinical research. After collecting enough data, a report can be formed and the IND application documents can be prepared. It is suggested here that the IND application preparation time must be sufficient. It is best to prepare the IND application documents after the drug candidate is determined. There are many IND-related guidance documents and forms on the FDA official website (https://www.fda.gov/ drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/investigationalnewdrugindapplication/default.htm), you can learn while following up the project, so that the content of the application documents is clear and reasonable.
Before the applicant submits the IND application, he can voluntarily hold an important meeting with the FDA, namely the Pre-IND meeting, within 60 days after the application date. At this meeting, applicants can discuss with relevant FDA experts to determine the trial plan, discuss the scope of the phase I clinical trial design, the pediatric research plan for new drugs, whether the existing CMC information is sufficient, and so on. Of course, not all INDs need to convene this meeting, and some simpler IND applications do not need to be convened, but for those serious life-threatening diseases, new indications, etc., it is better to discuss the more insurance together…
After the above process is fully prepared, the IND can be submitted to the drug review department. In the United States, FDA project supervisors will forward the IND application to a review team composed of chemists, pharmacologists/toxicologists, clinicians, statisticians, and pharmacokinetics. The FDA will also review the safety of the IND within 30 days to ensure the safety of subjects during the trial. During this period, the FDA may require the reporting company to provide additional information and instructions, so applicants are best to make sufficient and appropriate data reserves in advance. If the FDA does not have any feedback within 30 days, the company can determine that the IND has passed the review and carry out the corresponding clinical trials according to the content of the application.
The background information to be considered in an IND application mainly includes four parts: the structural source of the compound, the pharmacological classification, the current status of research/marketing of similar drugs at home and abroad, and the basic status of the application project. Among them, the structure source mainly analyzes whether the compound is a new structure, an existing core structure modification, or a salt or ester of a marketed drug; the pharmacological classification is mainly combined with the research information provided by the applicant to determine whether it is a new mechanism, a new target or a new target. There is a mechanism or target of a drug. The above two points can be used to make preliminary judgments on its druggability and risk. For example, compounds with new structures, new mechanisms and new targets, the hidden development risk is much higher than the salt or ester formation of the marketed drugs. The possibility of being a medicine is also relatively low.
On the one hand, it may be to increase the availability of medicines, and on the other hand, it may be to solve the problems of existing medicines. Therefore, it is necessary to fully understand the target indications, including epidemiological evidence, disease severity and prognosis, current treatment methods and their shortcomings, and the development trend and experience of target indication drugs. In addition, it is necessary to understand the relevant diagnosis and treatment guidelines, drug development trends and the potential of the varieties under application, etc.
The main concern is whether the applicant has formulated the overall plan of the human trial research path, at which stage the applied research is in the planning, or there is no overall or phased research plan, only the application project itself has put forward the research questions/plans at a specific stage .
Understand the basic information of the application project, such as which phase/phase of human clinical trials to be carried out, including the amount of the sample, the duration of the trial, the dosing plan, the research scale (location), etc., to provide for the follow-up technical evaluation Reference basis.
Pay attention to the basis for supporting the current application, mainly considering the basis of validity. These supporting evidences mainly come from clinical trials (in the process of clinical trials of a certain compound, new clinical applications may be discovered, and new clinical applications may be discovered. Applications are often far from the original expected indications), basic research (basic research starting from the laboratory is still the standard path for most drug development, if the supporting information comes from basic research, you need to pay attention to the evidence of this information Intensity) or other relevant information (in some cases, especially when drugs with the same mechanism of action have been successfully marketed and there is no reasonable model, bridging information can be used to obtain supporting information for the application, such as mechanism research, drug metabolism Distribution of research information, etc.).
Judging from the current international research trends, the development of new drugs is a research evaluation model dominated by clinical trial programs. The staging of traditional clinical trials is becoming more and more obscure. Whether a drug can be marketed depends on whether the data obtained can support the evaluation of its safety and effectiveness, rather than whether complete clinical trials have been carried out. The content and schedule of non-clinical and pharmaceutical research should be determined according to the content of the clinical trial to be carried out, and research and evaluation are accompanied by research and evaluation while making decisions. The overall and scientific evaluation of the research program is mainly to evaluate the proposed clinical program. The content includes basic research hypothesis, research population, efficacy indicators, research cycle, drug delivery method and basis, control bias means, data management, Applicant’s risk control measures, etc.
Based on the proposed clinical trial plan, evaluate the compound’s own research data, the research data of similar compounds or drugs with the same mechanism of action, and the safety information related to the preparation, and judge whether the existing data (self + literature) can support the safety of the clinical trial , And put forward the risk control points that may need attention. The risk mainly comes from research on the compound itself, similar compounds, and similar mechanisms.
Whether the quality of the test substance used in early clinical trials is comparable to the quality of the test substance used in non-clinical trials, and whether the quality of the test substance used in subsequent clinical trials is comparable to the quality of the test substance used in the previous clinical trials, pay attention to the test substance The nature and content of impurities.
Based on the above evaluation of the proposed clinical trial plan and safety information, analyze whether there are sufficient risk control measures in the clinical trial plan. The specific content includes: whether the subjects in the clinical trial design are healthy volunteers or select the corresponding patient group based on the safety risk signals and the clinical trial itself; for the known potential risks, whether the monitoring procedures are complete, whether the exposure can be effectively exposed and can be identified Safety signals, whether there are unacceptable system risks; whether the clinical trial plan has formulated the necessary risk control methods based on risk analysis; whether there is a mechanism for evaluating and improving the risk control methods.
In the development of innovative drugs, pharmacy-related changes are almost inevitable, especially in the early development stage, where changes occur more frequently. Generally, in the pre-clinical and early clinical research stages, pharmaceutical research is mainly to provide quality-guaranteed research samples for the above research; with the advancement of clinical research, pharmaceutical research is committed to definite, stable, reproducible, and industrialized production Process and build a complete drug quality control system; combined with clinical research/treatment needs, scale-up production needs, and continuous deepening of drug understanding, the dosage form, specifications, prescription process, analysis methods, quality standards, etc. are adjusted and optimized.
Summarize the aforementioned background information and evaluative information, and judge whether the evidence currently obtained supports the research plan drawn up by the applicant. If it is supported, it is necessary to clarify the scope of clinical exploration supported, the corresponding risk prompts, the supportive research that needs further follow-up and other related aspects such as the work of PI, CRO, and ethics committee. If the existing evidence does not support the proposed clinical trial protocol, it is necessary to clarify the deficiencies and follow-up issues that should be paid attention to.
As we all know, there is a possibility of failure in the entire IND process. According to reports, the overall failure rate of IND is more than 90%. Among them, the failure rate in phase I clinical trials is more than 95%, phase II and phase III are about 60% and 25%, respectively. There are many reasons for the failure of IND. In 1991 and 2000, the data of 10 large pharmaceutical companies showed that the rate of cases where the developed drugs were eliminated due to clinical safety factors was about 10% and 12%, respectively, due to clinical effectiveness. The eliminated cases were approximately 30% and 28%, respectively. The eliminated cases due to unsatisfactory pharmacokinetics or bioequivalence factors were approximately 40% and 8%. The eliminated cases due to commercial factors were approximately 5% and 28%. 21%, the cases that were eliminated due to non-clinical toxicity were about 11% and 21%, and the cases that were eliminated due to other uncertain factors were about 4% and 8%. In addition, the data in 2000 showed that the rate of being eliminated due to prescription factors and price factors was about 5% and 9%, respectively. Based on the analysis of the above reasons, the top three factors leading to the failure of drug development are pharmacokinetics, clinical effectiveness and toxicity. In terms of stages, the rate of being eliminated due to insufficient clinical effectiveness is equivalent in phase II and phase III clinical trials, basically between 50% and 55%. The rate of elimination due to safety is comparable in phase I and phase II clinical trials, about 30%.
As far as my country is concerned, there are not many Class 1 new drugs on the market in China. Furthermore, there are not even Class 1 new drugs in the true sense similar to large foreign pharmaceutical companies. However, the current domestic environment is pressing for drug research and development to catch up with developed countries such as Europe and the United States as soon as possible. Therefore, the spring of domestic innovative drugs seems to have really come. However, the development of innovative drugs nowadays is different from the past, and its difficulty is getting higher and higher, and the soft and hard strength of domestic new drug research and development is not enough to catch up with the current requirements for truly innovative drugs. Therefore, whenever a relatively heavyweight IND application is found, everyone will pay a lot of attention to it, hoping that it can produce high-quality fruits, improve the domestic innovative drug environment, and increase the confidence of new drug research and development personnel. Innovative drug research and development can definitely be regarded as a job that is extremely exhausting both mentally and physically, but this job also inspires every new drug researcher to fight against the disease. I hope that every new drug researcher can bear this. Lonely, with each IND application, they have grown into researchers who are truly worthy of new drug research and development positions. Of course, if you can get a further NDA, it will be even more perfect! Encourage each other!
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