Discussion: Contents and procedures of "development and evaluation” of innovative drugs

In recent years, under the guidance of national policies, the development of domestic innovative drugs has been extremely hot. Many pharmaceutical companies have opened their own innovation departments, and whether it is to engage in projects on their own, or to buy projects in the BD department, and to develop innovative drugs, it seems that it has become one of the necessary businesses for a pharmaceutical company.

01
What are the tasks of “development and evaluation” of innovative drugs?

The “development and evaluation” of innovative drugs follows the domestic two-batch procedure. The first stage is IND application approval, and the second stage is NDA application approval. In the IND stage of a new drug, the drug-ready properties of the selected candidate drug must first be investigated, and then the preclinical pharmacology, pharmacology, and toxicology will be developed successively, and the preclinical evaluation content will be comprehensively formed; while the NDA stage is to further improve the IND data On a solid foundation, combined with scientific and detailed clinical data and statistical results, it proves that the developed varieties are safe, effective, and controllable in quality, in order to obtain marketing approval from the National Bureau.

Ø Pre-clinical evaluation ~ druggability
This stage is the end of a process and the beginning of a milestone; the end is the screening of hundreds of compounds before the development, lead determination, lead modification and optimization, etc., and the beginning is the identification and development of candidate drugs. Its main tasks are the research of druggability and preclinical pharmacy, pharmacodynamics and molecular mechanism, pharmacokinetics and safety evaluation of new drugs.

Candidate drugs can be derived from synthesis, can be derived from natural product extraction, or can be obtained from compound libraries. With the development of science and technology and the continuous in-depth understanding of diseases, target-based drug design has become an important way to discover new drugs; drug targets generally include enzymes, receptors, ion channels, nucleic acids, etc., and research generally involves in-depth understanding of the target , Activity, and disease relationship, and actively design new chemical entities (NCE) that have agonistic or inhibitory effects on the target as candidates. The new drugs obtained by this method have the characteristics of clear mechanism of action, clear drug effects, and predictable adverse reactions to a certain extent. However, this method often requires the synthesis of a large number of compounds, which involves another aspect of preclinical evaluation, namely, finished drugs. Sexual research.

The druggability, first of all, is preliminary screening, requiring simple, clear, and effective experimental models to quickly expose the expected compounds. The focus of the preliminary screening is generally on the two aspects of pharmacological activity and toxicity, in order to obtain candidate drugs with low toxicity and high activity for further systematic evaluation. After the drug-candidate problem is basically determined, further systematic reviews in pharmacy, pharmacology, toxicology, etc. must be carried out.

Ø Pre-clinical evaluation ~ pharmacy evaluation
The specific research items of pharmacy evaluation involve the research of medicinal chemistry, pharmacy, drug content and quality standards.

The part of medicinalization mainly includes research on the confirmation of candidate drug structure and physical and chemical properties (crystal form, stability, solubility, hygroscopicity, solubility, viscosity, etc.), and the conversion and cost of feasible synthetic process routes in the laboratory to mass production. Reasonable control and so on. Although this part of the work is gradual, it is easy to add a certain amount of work to the quality department during the process of enlargement, so it is best to realize the true meaning of the process route in the small test stage.

In the part of pharmacy, in vitro dissolution and bioavailability studies are more important in the research. The former is one of the basis for the selection of dosage forms, while the latter is of great significance in investigating drug absorption in the body, predicting drug efficacy, and guiding clinical use; prescription dosage forms And the preparation process research will provide clinical preparations that are safe, effective, stable, biologically active, uniform and practical. Although the work at this stage is after the raw materials, quality, and even GLP, if excessive “late intervention”, it is easy to affect the progress of the entire project. Innovative drugs are different from imitations, and everything can happen.

Drug distribution and quality standards can be said to run through, and with the development process, methods and standards suitable for different stages are formed. From the official development of APIs, the analytical quality department began to develop testing methods for starting materials, intermediates, APIs, and impurities, and carried out method verification along with the progress, and then proceeded to step-by-step formal testing. This process not only requires constant communication with the synthesis team, but also with the preparation team, which takes a long time.

Ø Pre-clinical evaluation ~ pharmacology
Pharmacological research at this stage includes: main pharmacodynamics, pharmacokinetics, safety pharmacology, and preliminary mechanism of action, etc., mainly to understand the impact of new drugs on the main body systems and possible molecular mechanisms.

The main pharmacodynamics generally requires at least two or more animals (at least one is non-rodent), two or more methods, and two routes (one is the route of clinical administration and the other is the route directly into the circulation), 3 doses, blank control, positive control and model control, etc.; pharmacokinetics generally requires 3 doses, providing conventional pharmacokinetic parameters, model chamber types and distribution and excretion rules, etc.; safety pharmacology, generally requires 2~3 effective Dosage, clinical route of administration, at least observe the effect of the drug on the cardiovascular system, respiratory system and nervous system.

Ø Pre-clinical evaluation ~ Toxicology
Pre-clinical toxicology evaluation is another core content of new drug evaluation, and it is also a link that attracts much attention in new drug evaluation. The level of drug toxicity directly determines whether a new drug can be clinically tested and even marketed. All of the pre-clinical toxicology evaluation The work is required to be completed in a laboratory with GLP qualification, and a result report will be issued by the laboratory. The content of GLP research mainly includes more than ten items such as acute toxicity, long-term toxicity, toxicology, special toxicity, topical drug toxicity, allergy test, irritation test and drug dependence test, but not all drugs need to do all tests , This often needs to be implemented after reasonable selection based on the intended application scope of the drug.

Ø Results of pre-clinical evaluation and subsequent clinical evaluation
The final manifestation of the above work is to complete all the materials required for the clinical trial application and enter the IND stage. If the clinical trial approval is successfully obtained, the clinical evaluation work can be started immediately.

The task of clinical evaluation is to confirm the safety and effectiveness of new drugs on the human body, and at the same time complete the corresponding follow-up pharmacology, toxicology and pharmaceutical work. Clinical evaluation is another key link in the evaluation of new drugs. It is impossible for clinical ineffectiveness or too much toxicity relative to the efficacy to be approved for marketing. Its main content is the observation of clinical efficacy, toxicity and adverse reactions. According to the current regulations in my country, it is divided into phases I to IV clinical research: Phase I is to conduct research on a small number of normal healthy humans, and the purpose is to study the human body’s tolerance to new drugs and give A safe range of administration is provided, and human pharmacokinetic parameters are provided; Phase II is a randomized double-blind controlled study, which mainly observes drug efficacy and adverse reactions in humans; Phase III is a clinical study, which is mainly an expanded scale clinical trial Trials; Phase IV continues to expand clinical trials, special clinical trials, supplementary clinical trials and adverse reaction observations after the new drug is approved for marketing. Whether a new drug can be successfully marketed depends on the results of clinical evaluation. The final manifestation of the work at this stage is to complete all the materials required for the production of the new drug and enter the NDA stage.

02
The procedural logic of “development and evaluation” of innovative drugs

On the basis of a brief overview of the main content of the “development and evaluation” of innovative drugs, let’s talk about what SOP is based on during this process.

Ø Systematic development of innovative drugs
First of all, the development and evaluation of new drugs is a system; it requires multiple modules and multiple disciplines to work together, coordinate operations, and charge together; for the evaluation of new drugs, the various disciplines are mutually connected, complementary, and mutually complementary. Restrictions, there are even more innumerable factors between different units that can affect the progress and progress of the evaluation work.

Many scientific researchers are trying to formulate a scientific, reasonable and feasible workflow in order to improve work efficiency so as not to delay progress. However, because each new drug is different in variety and the problems that arise in the evaluation process are very different, there is currently no uniform plan that can be applied to all types of drugs and can be accepted by the heads of various disciplines. We can only design a relatively principled and generalized procedure for the whole process of new drug evaluation, which is generally applicable to all drugs, and can reflect the commonality of drug evaluation work while also taking into account the individuality of specific drugs as much as possible. Nowadays, most plans are made in accordance with the process of two domestic reports and two batches.

Ø Focus on the logical main line of “pharmacology-clinical data”
In addition to pharmaceutical research, pre-clinical evaluation is based on pharmacological evaluation, which can be divided into three periods: preliminary pharmacodynamic screening, main pharmacodynamic testing, general pharmacological research and possible mechanism research; clinical evaluation is divided into I to In Phase IV, with these 7 periods as the main process, the evaluation work of each discipline will be carried out accordingly; IND data will be presented when the preclinical phase is over. After the clinical phase II is over, you can summarize and organize the data and submit it to apply for trial production; and after the clinical phase III, you can apply for conversion to formal production.

An excellent person in charge of new drug evaluation (requires a strong voice) needs to have the ability to organize and coordinate all aspects of work. That is to say, the overall arrangement of the work of various disciplines should be reasonable and detailed, so as to determine the personnel, content and time, and determine which evaluation items should be first and which can be delayed. Even though sometimes from the perspective of a certain discipline, it saves time, effort, and money to complete all experiments at once, but considering the quality and speed of the overall evaluation, you may have to stop and wait for the evaluation results of other disciplines to make a decision. How to proceed in one step, so the new drug evaluation work also has the problem of partial compliance with the whole, which requires the thinking and overall planning of the person in charge QbD.

Ø Examples of arranging tasks in various disciplines
If the work of each discipline corresponds to the pharmacological evaluation of each period, we can see the requirements of the new drug evaluation for the relevant disciplines at different stages. Conversely, various disciplines can also understand the work they should complete based on the evaluation stage of the new drug at that time, and use systematic thinking to determine the progress of their own modules.

For example, the acute toxicity evaluation should be completed in the preliminary screening stage, to grasp the toxicity of the new drug, the symptoms of acute poisoning and the treatment measures, and the ratio of LD50 to ED50, which is the safety factor, can be used to preliminarily determine the size of the drug’s safety range; and long-term toxicity The evaluation should be completed in the pre-clinical stage in order to provide the basis for the dose and adverse reaction testing of clinical drugs; the identification and content determination of the raw material should be carried out before the main pharmacodynamics, and the drug effect obtained by using drugs with inaccurate content or even without content specifications The results of the scientific evaluation must be meaningless; the work before the determination of the dosage form, such as crystal size, crystal form, dissolution rate, drug and excipient interaction, and stability test, should also be done early because of the relationship between these important physical and chemical properties. To the repeatability and reliability of the evaluation results. It is generally believed that the pre-clinical pharmacokinetic evaluation is generally carried out at the same time as the main pharmacodynamic evaluation. It is best if it can be completed before the start of the long-term toxicity test, because the results of the above two evaluations have a significant The search for target organs and the determination of organs for pathological examination have reference value.