The development of innovative drugs is an extremely exploratory research process, which usually starts from the unknown and carries out drug screening and discovery based on unmet clinical needs. Different from generic drugs, research on innovative drugs is gradually carried out with different stages. The depth of each stage of research usually corresponds to the corresponding degree of strictness of the review, so as to avoid unnecessary over-development and save all aspects. H. In my country, although the development of innovative drugs started late and is not yet mature, the overall trend is catching up with Europe, America and Japan, and the details of each link are also being improved. For example, the “pharmaceutical research” in the IND application to be discussed below is one of them.
As early as 1995, CDER and CBER of the U.S. Food and Drug Administration issued the IND phase drug guidelines “Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Product”, this guide clarifies the data requirements of 312.22 and 312.23 in 21 CFR on the initial entry of drugs into clinical research trials in the United States, allowing the data and depth of various studies submitted in the IND phase, with great flexibility.
In 2003, the FDA issued a guideline “INDs for Phase 2 and Phase 3 Studies”, which further provided applicants (IND phase) with relevant suggestions and requirements on Phase II/Phase III clinical chemistry, production, CMC information, etc.
In 2008, the FDA issued a guideline “CGMP for Phase 1 Investigational Drugs”. The guideline elaborated on the implementation of cGMP in the production of phase 1 clinical trial samples. It is recommended to adopt the principle of drug quality control (QC) as part of cGMP to ensure phase 1 clinical trials. Test the quality and safety of the samples.
In 2013, the FDA again issued a guideline “Investigational New Drug Applications (INDs)-Determining Whether Human Research Studies Can Be Conducted Without an IND”. The guideline is designed to help clinical applicants determine whether relevant studies must be Research, such as 21 CFR 312; and specified when an IND application is required and under what circumstances an IND application is not required, and a certain scope of application has been determined.
According to the detailed content of the relevant guidelines issued by the US FDA, at different clinical application stages, it has detailed segmented research requirements for the raw materials, stability, quality, formulations, etc. of the innovative drug-pharmaceutical part. The details are as follows:
☆☆Phase I clinical
Preparation process~Provide a brief summary of the synthesis process research, explain the existing trial production scale, the synthesis route diagram suggests to clarify the reaction conditions of each step, the reagents, solvents, catalysts, etc., and it is recommended to start paying attention to the accumulation of quality data on key starting materials; Due to the difference in the refining process, the impurity spectrum, crystal form, particle size, etc. of the product may be affected, so attention should be paid to the purification/refining method of the crude product.
Characterization ~ At this stage, it is sufficient to provide preliminary research data supporting the chemical structure; explain the physical and chemical properties that may affect safety, such as solubility (in different pH solutions), particle size, crystal form, etc. It is recommended to determine the medicinal crystal form in the early clinical stage, but the particle size needs to be combined with the advancement of clinical research to continuously accumulate data.
☆☆Phase II/III clinical
Preparation process ~ Submit the changes in the preparation process and related research materials to evaluate the impact of the changes on the quality and safety of the product; the process control of the production steps (such as the purification step of the fermentation product) to ensure the safety of the product should be clearly described; provide Quality control information (source, analysis method, test result) of starting materials, detailed production process information should be provided for key starting materials with complex structure; control information of key steps and intermediates should be provided.
Characterization~Provide reasonable support for the chemical structure of the drug. Single crystal X-ray diffraction, conformation analysis, etc. can be provided in Phase III; combined with the dosage form characteristics and drug characteristics of the clinical trial preparations, provide further complete information on the pharmacological properties of the raw materials, including solubility , Crystal form, particle size, permeability, optical rotation, moisture absorption, partition coefficient, ionization constant, etc. For oral solid dosage forms, it is recommended to study the permeability of the bulk drug as soon as possible, understand its BCS classification, develop the formulation process and release in vitro The establishment of the method is very helpful.
☆☆Phase I clinical
Provide existing stability test results and follow-up stability research plans; for preparations that are reconstituted, diluted or mixed for multiple applications, stability studies in use should be carried out; it is recommended to conduct tests on influencing factors to understand the drug’s performance Intrinsic stability and potential degradation pathways help the selection of stability test conditions and the investigation of analytical methods. The results of existing stability studies should support the proposed clinical research and ensure the stability of the drug quality during the proposed clinical trial.
☆☆Phase II/III clinical
Summarize the stability test data of representative batches that have been obtained; describe the chemical and physical sensitivity of the API, such as light sensitivity, hygroscopicity, etc., and potential degradation pathways. Phase I and Phase II clinical trials usually have a long period, and the stability of the samples to be used in clinical trials is very limited. It is recommended to submit relevant supporting research data, such as pre-clinical or early clinical trial prescriptions and batches of similar processes. And the stability research results of smaller batches. After entering phase III clinical trials, stability tests should usually be carried out in accordance with the guidelines to facilitate the application of NDA.
☆☆Phase I clinical
List the items, methods and acceptable limits of the quality standards. It is recommended to conduct preliminary verification of the applicability of safety related substances, genotoxic impurities and other testing methods, and preliminarily define the impurity spectrum; the proposed limit should be based on the accumulation of existing batch analysis data, and the impurity level of clinical samples shall not exceed the animal safety test The level of corresponding impurities supported by the data; provide batch analysis data of existing batches (such as safety evaluation, stability test, etc.) and batches to be carried out in clinical trials (if any).
☆☆Phase II/III clinical
Provide a summary of part of the verification results of the analytical method (listable, such as specificity, precision, accuracy, linearity, limit of quantification/limit of detection, etc.); continue the identification of impurity profiles; new impurities and preparations resulting from changes in the synthesis process of APIs Qualitative and quantitative research on the degradation products discovered by Zhongxin. It is recommended to determine the main impurities of the API and the main degradation products of the preparations when applying for phase I and II clinical trials; re-evaluate the quality standards and acceptability limits of the previous phase I or phase II, according to the current Further evaluation and adjustment during the research phase. For poorly soluble oral solid preparations, it is recommended to accumulate the particle size distribution data of the drug substance used in the preparation, establish the correlation between the data obtained in the early and late stages of drug development and the in vivo efficacy; establish the dissolution/release method, and select the medium and test method based on the characteristics of the drug. It is recommended to investigate the dissolution/release behavior of pre-clinical test samples, phase clinical test samples, and stability test samples to establish the correlation between the data obtained in the early and late stages of drug development and the in vivo efficacy. Submit batch analysis data of various clinical trial samples.
☆☆Phase I clinical
The usual dosage forms are relatively simple. For example, oral preparations are powdered into capsules, or prepared into suspensions, solutions, etc., to facilitate the exploration of dosages. There are still great uncertainties in the dosage forms and prescription processes at this stage, and they are not subject to pharmaceutical evaluation. The key point is to ensure the stability and safety of clinical trial samples. However, for sterile preparations, for safety reasons, detailed sterilization/sterilization process conditions should be provided, and the preparation process should ensure the sterility of the product. Attention should be paid to the differences in the production and characteristics of the preparations to be used in clinical trials and the preparations used in toxicology trials, and the extent to which these differences may affect safety. In short, it is necessary to ensure that the drugs used in preclinical animal trials, clinical trials, etc. The quality is comparable. In addition, it should be explained whether the preparation process of the raw materials and preparations shows any potential human risk signals. If so, these potential danger signals should be analyzed and the monitoring plan should be elaborated.
☆☆Phase II/III clinical
Submission of changes in dosage forms, prescriptions, processes and related research data during Phase I or Phase II clinical trials. Quality characteristics such as dissolution behavior may have potential clinical relevance. Please pay attention to the impact of changes on these quality characteristics, and evaluate early clinical trial preparations and subsequent plans. Relevance of the formulation used. For Phase I and II declarations, if the key production steps have been clarified, the control of the key steps and the control information of the intermediates should be recorded. Phase III clinical trials are the most important part of the trial to confirm the safety and effectiveness of drugs. The samples used in phase I and II clinical trials are the key batches related to the safety, effectiveness and product quality attributes of the drugs, which will be useful for future new drug applications (NDA) It is very important to develop a comprehensive quality control system when applying. It is recommended to pay close attention to the CMC related information of phase I and II clinical trial samples. It is usually based on the planned commercial production to reasonably arrange the production of phase I and II clinical samples and other pharmaceutical research work, try to avoid major changes that affect product quality before NDA, and strengthen the collection of process control information and key quality information .
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