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MindMap Gallery Clinical Pharmacology Chapter 2 Research and Development of New Drugs and Clinical Research of Drugs

Clinical Pharmacology Chapter 2 Research and Development of New Drugs and Clinical Research of Drugs

Clinical Pharmacology Chapter 2: Mind map of new drug research and development and drug clinical research, classification management of new drugs, drug research and development and clinical trial focus.

Edited at 2024-04-07 07:52:29

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Clinical Pharmacology Chapter 2 Research and Development of New Drugs and Clinical Research of Drugs

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Outline

Chapter two Clinical trials and clinical pharmacological evaluation of new drugs

Classification management of new drugs

The lower the level, the more difficult it is

Level 1: Drugs not marketed domestically or abroad (original new drugs)

Level 2: Drugs that have changed the route of administration and are not marketed domestically or abroad.

Level 3: Drugs not marketed in China

Level 4: Changes the acid radicals, bases, and metal atoms of drugs already on the market, but does not change the pharmacological effects of raw materials and their preparations

Level 5: Change the dosage form of domestically marketed drugs without changing the route of administration

Level 6: APIs and their preparations that have national standards

The development process of new drugs

drug discovery

Evidence-based experience summary

Basic research breakthrough

serendipity process

Drug target and new compound discovery

Preclinical studies

in vitro studies

Cell level model

molecular level model

gene chip technology

In vivo animal experiments

Disease model research

pharmaceutical research

1. Research on production technology of API

2. Preparation prescription and process research

3. Confirmation of chemical structure or composition studies

4. Quality research: including physical and chemical properties, purity inspection, solubility, content determination, etc.

5. Quality standard draft and drafting instructions

6. Stability studies

7. Samples for clinical research and their test reports

8. Product packaging materials and basis for selection

clinical toxicology research

pharmacological content

Pharmacodynamic test

Pharmacodynamic testing: should be based on in vivo animal testing, and when necessary, cooperate with in vitro testing to confirm its efficacy from different levels.

General pharmacological research

Nervous system: activity, behavioral changes and impact on the central nervous system

Cardiovascular system: impact on electrocardiogram and blood pressure, etc.

Respiratory system: Effects on respiratory rate, rhythm and amplitude.

Pharmacokinetic studies

toxicology research

Acute toxicity test (LD50, maximum dose test)

Chronic toxicity test (conditions: animals, dose, method and route of administration, experimental period)

Special toxicity tests (reproductive toxicity tests): carcinogenicity tests, mutagenicity tests, teratogenicity tests

Chemical Processing of Drugs

clinical research on drugs

Including phase I, II, III and IV clinical trials, bioequivalence trials and post-marketing drug re-evaluation Purpose: To determine the safety and effectiveness of drugs and provide scientific basis for national approval of drug production

drug clinical trials Quality Management CodeGCP

Definition: GCP is the standard regulation for the entire process of clinical trials, including plan design, organization, execution, inspection, audit, recording, analysis, summary and reporting Purpose: To ensure the standardization of clinical trial processes, ensure scientific and reliable results, and protect the rights and safety of subjects

significance

1. Enable medical ethical principles to be implemented in clinical trials and fully protect the rights and health of subjects

2. Emphasize scientific standards, ensure the accuracy and reliability of test data, and provide scientific and true clinical data for drug clinical evaluation

3. Emphasizing quality control is an effective measure to improve the level of supervision and management of new drug research

4. It is a powerful measure to narrow the gap in drug clinical trials between developing countries and developed countries, and is conducive to the entry of innovative drugs from developing countries into the international market.

5. Conducive to the simultaneous implementation of international multi-center clinical trials

GCP management essentials

Contents of the informed consent form

1. The purpose of the clinical trial and the experimental procedures that subjects need to follow

2. The anticipated benefits of the trial and its important potential benefits and risks

3. Subjects may receive compensation and/or treatment when trial-related harm occurs

4. Subjects' participation in the trial is voluntary and they may refuse to participate or have the right to withdraw from the trial at any time at any stage without discrimination or retaliation.

5. Records related to subjects’ participation in clinical trials should be kept confidential and must not be made public

6. Subjects’ right to know during the trial, subjects are free to use drugs

Responsibilities of the Ethics Committee

1. Review drug clinical trial protocols

2. Review the researcher's handbook and informed consent form sample

3. Review the method used to select subjects, whether the information provided to subjects about the trial is complete and understandable, and whether the method of obtaining informed consent is appropriate.

4. Review of treatment and/or insurance provided

5. Review the researcher’s qualifications and experience

6. Regularly review the risk levels of subjects in ongoing clinical trials

Investigator Qualifications and Responsibilities

1. Have corresponding professional and technical positions and medical qualifications in medical institutions

2. Must be familiar with the pharmacological and toxicological properties of the drug being tested

3. Have rich experience or be able to receive academic guidance from experienced researchers in the unit

4. The relevant experimental conditions approved by the ethics committee should be explained to the subjects and informed consent should be obtained.

5. We are obliged to take necessary measures to ensure the safety of subjects. If an adverse reaction occurs, appropriate treatment measures should be taken immediately and reported to the drug regulatory authority.

Sponsor Responsibilities

1. Provide an investigator's manual, which includes chemical, pharmaceutical, toxicological, pharmacological and clinical (including concurrent and ongoing trials) information and data on the investigational drug

2. The sponsor appoints a qualified ombudsman acceptable to the investigator

3. Sponsors and researchers should quickly study adverse reactions that occur, take necessary measures to ensure the safety and rights of subjects, and promptly report to the drug regulatory authorities and health administration departments, as well as other researchers in clinical trials of the same drug. inform

4. Responsible for submitting the trial summary report to the State Food and Drug Administration

Organizational requirements: Establish an ethics committee of no less than 5 people, including both men and women (non-medical related, legal related)

Ethics committees and informed consent forms are the cornerstones of ensuring the safe and legal conduct of clinical drug experiments.

Procedural requirements: Develop a reasonable plan, subjects sign informed consent, and submit to the ethics committee for approval

Quality standards: Establish SOP, set clinical monitors, and establish correct experimental data processing and management standards

Researchers' responsibilities: accept the supervision of the ethics committee, promptly report serious adverse reactions and take timely and effective measures to protect subjects

Sponsor's responsibilities: Submit experimental protocol application, provide GMP-level test drugs, appoint inspectors, assist researchers in handling adverse reactions (unblinding if necessary), and compensate for adverse reactions caused by drugs

Experimental plan requirements: basis for the title, experimental purpose, experimental design plan, experimental plan shall be discussed and approved by the ethics committee

Clinical research on new drugs

Phase I clinical trial

Tolerance test

Generally conducted in healthy volunteers, when more toxic drugs should be administered in patients for their indications

Determine the minimum initial test volume

1. Refer to the clinical tolerance test (documentation) of the same drug and take 1/2 of the starting dose as the starting dose.

2. Refer to clinical tolerance tests of similar drugs and take 1/4 of the starting dose as the starting dose.

3. Starting from 1/10 of the clinical therapeutic amount of similar drugs

4. When there is no reference, the starting dose is calculated based on the preclinical animal test results.

1. 1/600 of the LD50 for sensitive animals or 1/60 of the lowest toxic dose

2. 1/600 of the LD50 of the two animal acute toxicity tests, and 1/60 of the long-term toxic dose of the two animals (the lowest one is the starting dose)

3. 1/100~1/50 of the minimum effective dose for the most sensitive animals

4. Larger starting amount (for anticancer drugs): 1/100 of the acute toxic LD50 in mice or 1/40~1/30 of the lowest toxic dose in large animals

Determine maximum dose

(1) The maximum single dose of the same drug, similar drugs, or drugs with similar structure

(2) 1/10 of the dose that causes poisoning symptoms or reversible changes in organs in long-term animal toxicity tests

(3) 1/5~1/2 of the maximum tolerated dose in long-term animal toxicity tests

(4) The maximum dose range should include the expected effective dose

(5) If there are scientific clinical research documents from abroad, you can refer to their maximum dosage for clinical treatment.

Termination test criteria

(1) Serious adverse reactions occur during dose escalation (affecting normal work, study, life, etc.)

(2) Half of the subjects experienced mild adverse reactions

(3) Half of anti-cancer drugs have serious adverse reactions

(4) When the maximum dose is reached and no adverse reactions occur, the trial should be terminated

Basic principles of dose escalation

The increment can be larger in the initial stage and gradually smaller in the later stage.

Fisher's increasing method: increase quickly at the beginning, then increase by 1/3, that is, 100%, 67%, 50%, 35%, and then increase by 1/3

Phase II clinical trial

Design Principles

(1) Representativeness: The determination of test subjects should comply with the principle of sampling population in statistics.

(2) Repeatability: The test results are accurate and reliable and can withstand repeated verification. When designing, attention should be paid to eliminating biases.

(3) Randomization: Randomization is the basic principle of clinical trials of new drugs. Randomized controlled double-blind trials eliminate objective bias factors, thus solving allocation errors and significantly improving the credibility of the trial.

(4) Rationality: refers to the experimental design that not only meets professional requirements and statistical requirements, but is also feasible

experimental design

1. Controlled experiment

Parallel controlled trials: suitable for diseases that may be cured by one course of treatment; the course of treatment is longer; the effect of the latter treatment drug will be different if it is administered after the first drug treatment; the source of cases required for the trial is not difficult; Have sufficient research power and conditions

Cross-controlled trial: According to the pre-designed test sequence, various treatments are implemented on the subjects one by one in each period to compare the treatment groups. difference between

2. Blind trial: It is one of the measures to control bias during the clinical trial process and when interpreting the results. It does not let doctors and patients know whether each specific subject receives the experimental drug or the control drug.

3. Placebo

Definition: Substances without pharmacological activity, such as lactose, starch, etc., are used as negative controls in clinical controlled trials. For some drugs with weak effects, placebo controls are established in order to accurately evaluate their effectiveness.

Placebo effect: Placebo can produce effects, such as analgesia and cough relief. The average effective rate is 35.2% ± 2.2%. Among them, the analgesic effect is the most obvious, with an effective rate of 60%.

The role of placebo control

1. Use as a negative control in randomized controlled trials so that the safety and effectiveness of new drugs can be evaluated under blind conditions.

When there is a positive control, a placebo control is also set up to monitor the sensitivity of the test method.

Exclude the role of psychiatric factors in drug treatment

Rule out spontaneous changes in the disease itself

Phase III clinical trial

To further verify the therapeutic effect and safety of the drug on patients with target indications, Evaluate the relationship between benefits and risks, and ultimately provide sufficient basis for approval of drug registration application

content include:

1. Research on the correlation between the concentration of new drugs in the human body and clinical pharmacological effects (drug efficacy and adverse reactions)

2. Pharmacokinetic studies on drug interactions with other drugs that may be used in combination with the drug

3. Research on the secretion and excretion of new drugs in human tissues and secretions

4. Pharmacokinetic research on new drugs in special populations, including research on the impact of factors such as impaired liver function and impaired renal function on human pharmacokinetics

Phase IV clinical trial

Expand clinical trials

clinical trials for special subjects

Supplementary clinical trials

Investigation of adverse reactions: Some adverse reactions with low incidence are not easy to be found in phase II and III clinical trials of new drugs and need to be continued to be investigated during phase IV clinical trials.