Drug clinical trials

Overview

Drug clinical trials are an indispensable step to confirm the effectiveness and safety of new drugs. Conducting drug clinical trials requires the cooperation of a variety of professional and technical personnel. A good clinical research team should include not only professionals in medicine, pharmacy, pharmacology, biology, biostatistics, etc., but also experienced document managers who are not medical professionals. In order to give full play to the role of these personnel, they should fully understand the research process of drug clinical trials and related regulations, standards and principles. Due to the particularity of the methods, means, and purposes of drug clinical research, for example, the participation of human subjects is required, and the data and results of drug clinical trials need to be approved by the drug regulatory authority, etc., drug clinical research is different from general scientific research. , Need to meet more regulations and follow more principles. It can be said that a good doctor with rich clinical treatment experience is not necessarily a qualified clinical researcher. Doctors and related personnel who are preparing and participating in clinical research should first understand the basic principles, concepts, and regulatory requirements for conducting clinical research in order to ensure that they are in an active position in future work.

Generally speaking, all drug clinical trials must follow the following three basic principles:

· ethical principles;

· scientific principles;

· GCP and current laws and regulations.

Phased trials

Phase I clinical trials

Preliminary clinical pharmacology and human safety evaluation trials are the initial phase of human trials for new drugs, also known as Early human trials. Phase I clinical trials include tolerance tests and pharmacokinetic studies, which are generally conducted in healthy subjects. Its purpose is to study the human body's tolerance to drugs, and through pharmacokinetic studies, to understand the laws of absorption, distribution, and elimination of drugs in the human body, so as to provide a basis for formulating dosing regimens for further treatment trials.

The human tolerance test (clinical tolerance test) is to observe the human body’s tolerance to the drug on the basis of detailed animal experimental research, that is, to find out the human body’s maximum tolerance to the new drug The received dose and its adverse reactions are a safety test in humans and provide an important scientific basis for determining the dose of a phase II clinical trial.

Human pharmacokinetics research (clinical pharmacokinetics) is to study the absorption, distribution, biotransformation and excretion of drugs in the human body, and provide science for the formulation of phase II clinical trials. Basis. Human pharmacokinetics observes the dynamic process of the content of drugs and their metabolites in the human body over time. This process is mainly described quantitatively by mathematical models and statistical methods. The basic hypothesis of pharmacokinetics is that the efficacy or toxicity of a drug is related to the concentration it reaches (such as the concentration in the blood).

Phase I clinical trials generally start with a single dose. Under strictly controlled conditions, a small number of test drugs are given to a small number (10-100 cases) of healthy volunteers who have been carefully selected and screened (for tumor drugs). Generally speaking, it is a tumor patient), and then carefully monitor the blood concentration, excretion properties, and any beneficial or adverse effects of the drug to evaluate the pharmacokinetics and tolerability of the drug in the human body. Volunteers are usually required to be hospitalized during the study period and are closely monitored for 24 hours a day. With the increasing understanding of the safety of new drugs, the dose of administration can be gradually increased, and multiple doses can be administered.

Phase II clinical trial

Phase II clinical trial is the preliminary evaluation stage of the therapeutic effect. Its purpose is to preliminarily evaluate the therapeutic effect and safety of the drug on patients with target indications, and also to provide a basis for the design of phase III clinical trials and the determination of the dosage regimen. The research design at this stage can adopt various forms according to specific research purposes, including randomized blinded controlled clinical trials.

This phase of clinical research focuses on the safety and efficacy of the drug. Use a placebo or a marketed drug as a reference drug to evaluate the efficacy of a new drug. In this process, the effect of the occurrence and development of the disease on the efficacy of the drug will be studied; the dose and schedule of the phase III clinical trial will be determined; more information Information on the safety of drugs.

Phase III clinical trial

Confirmation stage of therapeutic effect. Its purpose is 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 a sufficient basis for the review of drug registration applications. The test should generally be a randomized blinded controlled trial with sufficient sample size.

The sample size of this phase of the trial is much larger than that of the previous two phases. More sample size will help to obtain more information on drug safety and efficacy, and evaluate the benefits/risks of drugs , To provide support for the product to be approved for listing.

This phase of the trial is generally a random control trial (RCT) with sufficient sample size. The clinical trial will compare the relevant parameters of the test drug with a placebo (without active substance) or a marketed drug. The test results should be repeatable.

The goal of phase III clinical trials is to:

· Increasing the exposure of patients to test drugs, not only increasing the number of subjects, but also increasing the time for subjects to take drugs;

· Determine the ideal dosage regimen for different patient populations;

· Evaluate the overall efficacy and safety of the trial drug in the treatment of target indications.

This stage is the busiest and most concentrated part of the clinical research project.

Phase IV clinical trial

After a new drug is approved for marketing, further research is still needed to investigate its efficacy and adverse reactions under the conditions of widespread use. Post-marketing research is called "Phase IV clinical trial" in most countries in the world.

The first three phases of clinical trials conducted before marketing are evaluations of drugs in a small range and special groups of patients. Patients are strictly selected and controlled, so there are many exceptions. After being marketed, many different types of patients will receive treatment with the drug. Therefore, it is necessary to re-evaluate the efficacy and tolerability of drugs for most patients. In the post-marketing phase IV clinical studies, the research data of thousands of patients treated with the drug was collected and analyzed. In pre-marketing clinical studies, adverse reactions that have not been discovered due to their low incidence may be discovered. These data will support the data obtained in clinical trials and enable pharmaceutical companies to enable doctors to better and more reliably recognize the benefit-risk ratio of the drug to the "general population".

Regular phase IV clinical trials are required by the drug regulatory authority, and the research results are required to be reported to the drug regulatory authority. However, the developers of new drugs, especially their market expansion or sales, often organize some so-called seeding studies or marketing trials for the purpose of promotion. The main purpose is to let more doctors understand them through these studies. New products and encourage doctors to prescribe. For this reason, they often compare newly launched new drugs with similar competitive drugs. Such research is often not standardized and scientific in the design, implementation, evaluation and reporting of research results. In many countries, it is It is expressly prohibited by drug laws and regulations.

Another purpose of post-marketing research is to further broaden the scope of indications for drugs. The indications of the medicine are clearly defined in the product license. The medicine may also be used for other indications, but there must first be clinical trial data. For example, a new drug for the treatment of arthritis pain can be used in clinical trials to treat sports injuries, back pain, general pain, etc., to broaden its scope of indications. If these tests show that it is indeed effective in the treatment of these diseases, then you can apply to increase the indications of the drug. This kind of research broadens the scope of use of the drug, which can increase the potential market and sales of the drug. In some countries, the clinical research of this new indication is also classified as a "phase IV clinical trial", but some countries call it "phase III clinical trial B" (Phase IIIB), so the corresponding first indication is Phase III clinical trials are called "Phase IIIA" (Phase IIIA).

Bioequivalence test

Using the method of bioavailability research, taking pharmacokinetic parameters as an indicator, comparing the same or different dosage forms of the same drug. Under the test conditions, there is no statistical difference in the absorption degree and speed of the active ingredients in a human body test.

Preparatory conditions

There must be sufficient scientific basis for drug clinical trials. Before conducting a human test, the purpose of the test and the problems to be solved must be carefully considered, and the expected benefits and risks to the health of the subjects and the public should be weighed, and the expected benefits should exceed the possible damage. The selection of clinical trial methods must comply with scientific and ethical requirements.

Before conducting clinical trials, pre-clinical research data of the trial drug must be provided, including prescription composition, manufacturing process and quality inspection results. The pre-clinical information provided must meet the requirements for conducting the corresponding phases of clinical trials, and at the same time, the effectiveness and safety information related to the clinical trials that have been completed and the clinical trials in other regions should be provided. The preparation of clinical trial drugs shall comply with the "Good Manufacturing Practice for Drugs".

All investigators should have the professional expertise, qualifications and abilities to undertake the clinical trial, and be trained. Before the start of a clinical trial, the investigator and the sponsor should reach a written agreement on the trial plan, trial supervision, inspection and standard operating procedures, as well as the division of responsibilities in the trial.

The preparation conditions for drug clinical trials are summarized as follows:

·Approval for drug clinical trials approved by CFDA

·Specific drug inspection report

·Qualified drug clinical research institutions

·Qualified researchers

·Standardized design of new drug clinical trials Program

·Develop operational standard operating procedures (SOP for short)

Specification content

Regulations and regulations

To promote clinical trials in various countries The development of standardization, the ICH meeting held in Japan in 1996 formulated the first ICH document. This document not only combines the regulations of the United States, Europe and Japan, but also the regulations of the Nordic countries, Australia, Canada and the World Health Organization. Included. ICH documents are the global guidelines for clinical trials. Under the guidance of standardized regulations, clinical trials not only protect the safety of subjects, but also scientifically prove the effectiveness of new drugs.

On March 2, 1998, the People’s Republic of China "Regulations for the Administration of Drug Clinical Trials" (for trial implementation) was promulgated and formally implemented on September 1, 1999. It was re-promulgated on September 1, 2003 and renamed the "Quality Management Standards for Drug Clinical Trials." The formulation of my country's drug clinical trial management standards also refers to the clinical trial guidelines of WHO (World Health Organization) and ICH, and the requirements are basically in line with international standards. The promulgation of this standard will surely promote my country's drug clinical trials to reach the international level as soon as possible, and promote my country's new drugs to the world as soon as possible.

Procedure specification

1. New drug clinical research must be reviewed and approved by the State Food and Drug Administration (CFDA).

2. It must be carried out in a "drug clinical trial institution" approved by the State Food and Drug Administration.

3. The clinical trial must be presided over by a qualified medical expert.

4. It must be reviewed and approved by an independent ethics committee to confirm that the research complies with ethical principles, supervise the entire clinical trial process and ensure the legitimate rights and interests of subjects.

5. Before participating in the clinical research of the new drug, all patients have the full right to know and sign an informed consent form.

6. In clinical studies of anti-tumor drugs, patients who have failed conventional standard treatments are usually selected.

7. New drugs for clinical research should be provided to subjects free of charge.

Subject protection

In order to ensure the rights and interests of subjects in clinical trials, an independent ethics committee must be established and filed with the State Food and Drug Administration. The ethics committee should be composed of at least five people who are engaged in medical-related professionals, non-medical professionals, legal experts and personnel from other units, and have members of different genders. The composition and work of the ethics committee should not be affected by any participants in the experiment.

The trial protocol must be reviewed and approved by the ethics committee and signed for approval before it can be implemented. During the trial period, any modification of the trial protocol should be approved by the ethics committee; serious adverse events during the trial should be reported to the ethics committee in time. In the process of drug clinical trials, the personal rights and interests of subjects must be fully protected, and the scientificity and reliability of the trial must be ensured. The rights, safety and health of subjects must be higher than consideration of scientific and social interests. The ethics committee and informed consent are the main measures to protect the rights and interests of subjects.

Significance

For drugs, clinical trials are far more important than pre-clinical experimental studies (but pre-clinical studies are also very important because they are all in the development of new drugs An indispensable link), because the most basic properties of drugs--effectiveness and safety are ultimately tested by it. According to statistics, it usually takes more than 10 years for foreign research to study a new drug of a category I from the beginning of basic research until it is recognized and produced on the market. The average development cost of each new drug is about 1.2 billion US dollars, and the cost and time spent More than 70% is spent on clinical research, which shows the importance of clinical trials.

Clinical research on new drugs is very important. On the one hand, the evaluation of the efficacy of a new drug varies with different experimental animals; the response on animals is different from that on humans. On the other hand, the toxic reactions on animals and humans are also different. It can be said that clinical trials are very important in terms of effectiveness and safety, or capital investment. The determination of a new drug will ultimately depend on human trials. Therefore, clinical trials must be more cautious to prevent serious side effects from occurring, and to prevent the production of ineffective or even harmful drugs.

Existing problems

System reform

Since the middle of the last century, with the continuous discovery of many problems in medical and behavioral research, the protection of medical research subjects The person gradually entered the public eye. The most famous of these is the "Tuskegee Syphilis Test" in the United States. Since 1932, under the name of free treatment of syphilis, the U.S. Public Health Service has used 500 completely unaware black African Americans as test subjects to secretly study the harm of syphilis to the human body. In fact, these subjects did not receive any treatment. This project was not terminated until it was exposed by the media in 1972. At that time, 28 of the patients who participated in the trial had died directly from syphilis, about 100 died from complications of syphilis, 40 wives were infected, and 19 children contracted syphilis at birth.

The "Declaration of Helsinki" published in 1964 is regarded as the cornerstone of clinical research ethics. It stipulates: "Medical research can only be carried out when the test population can benefit from the results of the research."

Current situation in China

Since the 1990s, the Chinese drug clinical trial project The rapid increase, the number of subjects involved in a study ranges from as few as dozens to as many as tens of thousands. Data shows that more than 800 new drugs are tested in humans every year in my country, involving about 500,000 people.

In China, there is no special law on testing drugs. There is only one "Code for Quality Management of Drug Clinical Trials" that regulates testing behavior in China. This standard does not have a compulsory effect. There are also loopholes in the "Informed Consent" signed by the pharmacist and the hospital. At present, many clinical trial units do not respect in practice, or even violate the subjects’ right of informed consent, conceal the risk of drugs, unclear explanations, or only reach verbal informed consent.

Situation in India

After India relaxed drug trial restrictions in 2005, this "industry" has flourished. 150,000 Indians have participated in at least 1,600 clinical drug trials. Many well-known pharmaceutical companies in Europe and the United States are involved. Between 2007 and 2010, nearly 1,730 people in India died during or after participating in such trials.