What Does a Clinical Trial Specialist Do?

A drug clinical trial is any systematic study of drugs performed in humans (patients or healthy volunteers) to confirm or discover clinical, pharmacological, and / or other pharmacodynamic effects, adverse reactions, and / or absorption of the test drug , Distribution, metabolism and excretion, the purpose is to determine the safety and effectiveness of the test drug.

Drug clinical trials are generally divided into phase I, II, III, IV clinical trials and drug bioequivalence trials as well as human bioavailability ^[1] .

Chinese name: Drug clinical trials
Overview: Drug clinical trials are

Overview 2: Need for clinical drug trials
Staging test: Phase I clinical trial

Overview of drug clinical trials

Drug clinical trials are an essential step to confirm the effectiveness and safety of new drugs. Conducting clinical trials of drugs requires the cooperation of multiple professionals. A good clinical research team should include not only professionals in medicine, pharmacy, pharmacology, biology, biostatistics, etc., but also non-medical but experienced document managers. In order to give full play to their role, they should fully understand the research process of drug clinical trials and related regulations, standards and principles. Due to the particularity of methods, means, and objectives of drug clinical research, for example, the participation of human subjects, the data and results of drug clinical trials need to be approved by the drug regulatory department, etc., drug clinical research is different from general scientific research. , Need to meet more rules and regulations, follow more principles. It can be said that a good doctor with rich clinical experience may not be 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 will take the initiative in future work.

In summary, all drug clinical trials must follow three basic principles:

· Ethical principles;

· Scientific principles;

GCP and current laws and regulations.

Drug clinical trial staging

I Phase I clinical trials

The preliminary clinical pharmacology and human safety evaluation test is the beginning of human test of new drugs, also known as early human test. Phase I clinical trials include tolerance tests and pharmacokinetic studies, and are generally performed in healthy subjects. The purpose is to study the tolerance of the human body to the drug, and to understand the rules of drug absorption, distribution, and elimination in the human body through pharmacokinetic studies, and to provide a basis for the formulation of a drug regimen for further treatment trials.

The human tolerance test (clinical tolerance test) is based on detailed animal experiments to observe the tolerance of the human body to the drug, that is, to find out the maximum tolerated dose of the human body to the new drug and its adverse effects. Response is a safety test in humans, and provides an important scientific basis for determining the dosage of phase II clinical trials.

Human pharmacokinetics studies (clinical pharmacokinetics) provide a scientific basis for the formulation of dosing regimens for phase II clinical trials by studying the laws of the absorption, distribution, biotransformation, and excretion of drugs in the human body. 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 assumption of pharmacokinetics is that the efficacy or toxicity of a drug is related to its concentration (such as blood concentration).

Phase I clinical trials generally start with a single dose and give a small amount of test drugs to a small number (10 to 100 cases) of carefully selected and screened healthy volunteers (for tumor drugs, usually tumor patients) under strictly controlled conditions. , And then carefully monitor the blood concentration, excretory 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 monitored closely for 24 hours a day. As the understanding of the safety of new drugs increases, the doses administered can gradually increase and multiple doses can be administered.

II Phase II clinical trials

Phase II clinical trials are the initial evaluation of therapeutic effects. The purpose is to initially evaluate the therapeutic effect and safety of the drug in patients with target indications, and also to provide evidence for the design of phase III clinical trials and the determination of dosing schedules. The study design at this stage can take a variety of forms, including randomized blind controlled clinical trials, depending on the specific research purpose.

This phase of clinical research focuses on the safety and efficacy of the drug. Evaluate the efficacy of new drugs using placebo or a marketed drug as a control drug, in the process of studying the impact of disease development and development on the efficacy of the drug; determine the dosage and schedule of phase III clinical trials; get more Information on drug safety.

III Phase III clinical trials

Confirmation of treatment effect. The purpose is to further verify the therapeutic effect and safety of drugs 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 trial should generally be a randomized, blinded controlled trial with a sufficient sample size.

The sample size of this trial is much larger than that of the previous two trials. A larger sample size will help to obtain a wealth of information on drug safety and efficacy, evaluate the benefits / risks of the drug, and provide products for approval for marketing. support.

This phase of the trial is generally a randomized blind control trial (RCT) with a sufficient sample size. Clinical trials will compare the parameters of the test drug with placebo (without active substance) or marketed drugs. Test results should be repeatable.

The objectives of the phase III clinical trial are:

· Increased patient access to the test drug, both the number of subjects and the duration of the medication;

· Determine the ideal dosage regimen for different patient populations;

· Evaluate the overall efficacy and safety of the test drug in the treatment of the target indication.

This phase is the busiest and most focused part of the clinical research project.

IV Phase IV clinical trials

After a new drug is approved for marketing, further research is still needed to investigate its efficacy and adverse reactions under widely used conditions. Post-marketing studies are called "Phase IV clinical trials" in most countries around the world.

The first three phases of clinical trials conducted before marketing were for the evaluation of drugs in a relatively small and special group of patients. Patients were strictly selected and controlled, so there are many exceptions. After marketing, many different types of patients will be treated with the drug. It is necessary to re-evaluate the efficacy and tolerability of drugs for most patients. In post-marketing phase IV clinical studies, research data from thousands of patients treated with the drug was collected and analyzed. Adverse reactions that have not been detected in preclinical clinical studies may be detected because the incidence is too low. These data will support the data obtained in clinical trials, allowing pharmaceutical companies to better and more reliably recognize the benefit-risk ratio of the drug to the "general population" in treatment.

The formal phase IV clinical trial is required by the drug regulatory authority, and its 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 their research through these studies. New products are encouraged and doctors are encouraged to prescribe. For this reason, they often compare new drugs that have just been marketed with competitive drugs of the same kind. Such studies are often not standardized and scientific in the design, implementation, and evaluation of research results and reports. In many countries, Prohibited by drug regulations.

Another purpose of conducting post-marketing studies is to further broaden the indications for drugs. The indication of the drug is clearly defined in the product license. The drug may also be used for other indications, but the data of the clinical trial must be available first. For example, a new drug for the treatment of arthritic pain can be used in clinical trials to treat sports injuries, back pain, general pain, etc. to broaden its scope of indications. If these trials show that they are indeed effective in treating these conditions, you can apply for an increase in the indications for the drug. This research has broadened the scope of the drug, which can increase the potential market and sales of the drug. In some countries, the clinical studies of this new indication are also classified as "Phase IV clinical trials", but some countries refer to it as "Phase IIIB", then the corresponding first indication Phase III clinical trials are referred to as "Phase IIIA."

Bioequivalence test

Using the method of bioavailability research, using pharmacokinetic parameters as indicators, comparing the same or different formulations of the same drug under the same test conditions, whether there is a statistical difference in the extent and speed of absorption of active ingredients test. ^[2-3]

Drug clinical trial preparation conditions

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

Before conducting a clinical trial, preclinical research data for the test drug must be provided, including prescription composition, manufacturing process, and quality inspection results. The pre-clinical information provided must meet the requirements for conducting each phase of clinical trials. At the same time, the efficacy and safety data related to the completion of the test drug and ongoing clinical trials in other regions should also be provided. The preparation of drugs for clinical trials 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. Prior to the start of a clinical trial, the investigator and sponsor should reach a written agreement on the trial protocol, trial monitoring, audit and standard operating procedures, and division of responsibilities in the trial.

The conditions for preparation of clinical trials of drugs are summarized as follows:

· Obtained CFDA approval for drug clinical trials

· Medicine inspection report

· A comprehensive researcher's manual

· Qualified drug clinical research institutions

· Qualified researchers

· Standardized design of new drug clinical trials

· Formulate operable standard operating procedures (referred to as SOP)

Drug clinical trial specifications

Drug clinical trial regulations

In order to promote the standardization of clinical trials in various countries, 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 integrates the Nordic countries, Australia, Canada, and WHO specifications are included. The ICH file is a global clinical trial guideline. 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 "Practice Standards for the Administration of Drug Clinical Trials" of the People's Republic of China (trial) was promulgated, and it was formally implemented on September 1, 1999. On September 1, 2003, it was re-issued and renamed as "Good Clinical Drug Quality Management Practices." The formulation of China's pharmaceutical clinical trial management specifications also refers to the WHO (World Health Organization) and ICH clinical trial guidelines, and each of these requirements is basically in line with international standards. The promulgation of this standard will definitely promote the clinical trials of Chinese medicines to reach the international level as soon as possible, and promote the new medicines of our country to go to the world as soon as possible.

Drug clinical trial procedures

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

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

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

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

5. All patients have full right to know and sign informed consent before participating in clinical research of new drugs.

6. For clinical research of anti-tumor drugs, patients who have failed to be treated by conventional standard are usually selected.

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

Subject Protection for Drug Clinical Trials

To ensure the rights of subjects in clinical trials, an independent ethics committee must be established and filed with the State Food and Drug Administration. The ethics committee shall consist of at least five persons engaged in medicine-related professionals, non-medical professionals, legal experts and other units, and members of different genders. The composition and work of the ethics committee should not be influenced by any participant.

The test plan can only be implemented after it has been reviewed and agreed by the ethics committee and signed approval opinions. During the test, any modification of the test protocol should be approved by the ethics committee; serious adverse events during the test should be reported to the ethics committee in a timely manner. In the process of drug clinical trials, the personal rights of the subjects must be fully protected, and the scientificity and reliability of the trials must be ensured. Subjects' rights, safety, and health must take into consideration scientific and social interests. Ethics committee and informed consent are the main measures to protect the rights of the subjects.

Significance of drug clinical trials

For drugs, clinical trials are far more important than preclinical experimental research (but preclinical research is also important because they are indispensable in the development of new drugs) because the most basic attribute of a drug is effectiveness And security is ultimately tested by it. According to statistics, it usually takes more than 10 years to study a class of new drugs from the beginning of basic research until it is recognized and manufactured. The average development cost of each new drug is about 1.2 billion U.S. dollars. More than 70% is spent on clinical research, showing the importance of clinical trials.

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

Problems with clinical trials

Reform of drug clinical trial system

Since the middle of the last century, with the continuous discovery of many problems in medical and behavioral research, the subjects of protective medical research have gradually entered the public view. The most famous one is the "Tuschigi Syphilis Test" in the United States. Since 1932, the U.S. Public Health Agency has used 500 completely unknown African-American blacks as test subjects in the name of free treatment of syphilis, and secretly studied the harm of syphilis to humans. 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 participating 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 Helsinki Declaration, published in 1964, is regarded as the cornerstone of ethics for clinical research. It states: "Medical research can only be performed if the test population can benefit from the results of the research."

Drug clinical trials in China

Since the 1990s, China's drug clinical trials have increased dramatically, with a study involving as few as tens of subjects and as many as tens of thousands. Data show that there are more than 800 new drugs in human trials in China every year, involving about 500,000 people.

However, there is no special law on drug testing in China. The only domestic standard that regulates drug testing behavior is a "Code for the Quality Control of Drug Clinical Trials." This standard does not have a compulsory effect. "Informed Consent Forms" also have loopholes. At present, many clinical trial units have not respected in practice, and even violated the subject's right of informed consent, concealed the risk of drugs, had unclear explanations, or reached only verbal informed consent.

Drug clinical trials in India

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