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Time：2020-08-17Click：
[Abstract] This paper emphasized the attention of medical ethics in phase I clinical trials. Prior to the commencement of a Phase I clinical trial, the investigator will assist the sponsor in fully assessing the trial's risk benefits, scientifically designing the study protocol and setting up the relevant time points for the trial to facilitate timely safety information review and evaluation. During the implementation of the test, the subjects' vital signs and changes in various examination indicators should be closely followed and evaluated. The subjects' health should always be kept in the first place. The typical ethical issues involved in about 70 phase I projects have been completed by the organization are discussed.
[Key words] Clinical trial Phase I; Clinical research; Healthy subjects; Medical ethics
The level of drug r&d ability is an important manifestation of the international competitiveness of a country's pharmaceutical industry, and clinical research of drugs, as the final stage of new drug development, is the key to determine the success or failure of new drug development. Phase I trials are a crucial first step in a series of clinical trials that must be approved before a new drug can be used in the clinic.
In recent years, with the in-depth implementation of China's major science and technology project of "Major new drug Creation", independent innovative drugs have stepped into the clinical research stage one after another, and the requirement of international integration has prompted the construction and development of China's phase I clinical trial platform for drugs. Because phase I clinical trials have special ethical issues different from phase II and III clinical trials, it is imperative to comply with the "Quality Management Standards for Drug Clinical Trials" in clinical studies to protect the rights and interests of phase I subjects and ensure their safety. The author has been engaged in phase I clinical practice for many years and realized that while ensuring the quality of clinical research, the protection of the rights and interests of healthy subjects is in urgent need of strengthening and improving.
Medical ethics occupies a fundamental and strategic position in China's health undertakings. If medicine is separated from and loses this moral nature, medicine will not be medicine and its mission to serve human health will cease to exist. Because phase I drug trials are the first step in the transition from preclinical animal trials to human trials, healthy subjects are often recruited to complete the trials. The risks it faces (including adverse reactions and adverse events) have many uncertainties and unpredictability, which requires more comprehensive evaluation, scientific design, careful preparation and normative implementation by researchers and sponsors. Normative ethical review is the main safeguard for the protection of the rights and interests of stage I subjects, and the review of the phase I clinical study protocol and the informed consent form by the ethics committee is particularly important. The author will focus on the protection of the rights and interests of the subjects in the phase I clinical trial and explore management methods.
1. Fully and comprehensively evaluate the risk-benefit ratio of the test and scientifically design the research scheme
It is stipulated in the Quality Management Standard for Drug Clinical Trials that there must be sufficient scientific basis for drug clinical trials. Before conducting human trials, the purpose of the trials and the issues to be addressed must be carefully considered, and the expected benefits and risks to the subjects' and the public's health should be weighed, with the expected benefits outweighing the possible damages. However, since in phase I clinical studies with healthy volunteers, the subjects usually do not benefit from the clinical trial, it is necessary to pay attention to the possible damage to the subjects caused by the phase I trial and the expected public health benefits of the experimental drugs. It is obviously difficult for ETHICS committees to balance the risks and benefits at the micro and macro levels.
Phase I clinical trial protocols must be designed to meet scientific and ethical requirements. The investigator should be familiar with and familiar with the nature, action, efficacy and safety of the experimental drug (including relevant information on the preclinical study of the experimental drug), and should have access to all new information relating to the experimental drug discovered during the course of the clinical trial. For innovative drug, drug from phase I clinical trial is the animal experiment to the first step in human clinical trials, its safety and risk there is more uncertainty and unpredictability, which requires bidders and researchers from the characteristic of the drug, is closely related to the target indication of clinical indicators, adverse reactions and abnormal index found in animal experiments, such drugs in the clinical use of security incidents such as comprehensive analysis, strive to develop in the clinical trial scheme of safety observation index can cover all aspects of the observation information. In addition, the pharmacokinetic of dose escalation in the design and security research, should follow the international practice, the time interval between each dose group should be fully, to evaluate the safety of the drug, thorough and careful of ensuring we'll have enough time to monitor health subjects after taking drugs laboratory safety indexes such as change, to fully evaluate and confirm the participants were safe after the implementation of a high dose group of test; If abnormal laboratory test indicators or vital signs are found in the test, the healthy subjects should be followed up and observed for a sufficient time, and timely diagnosis, treatment and evaluation should be given to confirm that the safety is good and the risk is under control before the latter dose group is implemented. In addition, the investigator must conduct clinical trials in a medical facility with good medical facilities, laboratory equipment, and reasonably staffed facilities for handling emergencies to ensure the safety of the subject. Prior to the commencement of each clinical trial, the investigator should carefully evaluate the expected risk, burden, and benefit ratios of the subjects.
For some phase I trials that can only be performed in patients, such as some oncology drug studies, the determination of the initial dose and the number of participants is critical. New drugs used to treat tumours hold the promise of slowing or even curing the disease, while patients may also be exposed to the potential toxicity risks of treatment, particularly safety concerns. The difficulty in designing a phase I clinical trial of such a drug is determining the starting dose and the multiple of dose increments for the drug being tested. Too rapid a dose increase may cause toxicity in the patient quickly, while too slow a dose increase may prolong the duration of treatment for the subtherapeutic dose. Therefore, in order to not delay the treatment of patients and to expose as few patients as possible to effective treatment, the design of the initial dose, the length of the administration cycle, the number of people in each dose group, and the design of the efficacy observation indicators need to be carefully considered by researchers and sponsors.
In the review of the project research protocol, the ETHICS committee should focus its attention on all relevant aspects of the protection of subjects and pay high attention to the review of informed consent. In addition, during the follow-up review of the project, attention should be paid to the changes of adverse reactions, clinical safety data and clinical research risks in the current study. When necessary, on-site visits and real-time evaluation of researchers should be arranged to do a good job in the risk assessment of drug clinical trials and protect the safety and rights of the subjects.
2. Propose a complete emergency plan for the researchers to standardize the relevant links in the implementation of clinical research
"Drug tritoxicity", the pharmacological and toxicological characteristics of the drug itself and the existence of clinical individual differences determine that expected adverse reactions, adverse events and unexpected adverse events may occur in the process of drug clinical trials. In the process of drug clinical trial, researchers and sponsors should fully evaluate and predict the possible adverse events based on the preliminary research results and findings of the drug under study, and make corresponding rescue plans and emergency plans based on clinical diagnosis and treatment experience, and conduct emergency plan drills when necessary. Before the test, it is necessary to verify whether the rescue drugs are complete and whether the equipment is in normal condition, carry out each research step in accordance with the research plan and standard operating procedures, and record any findings in the study comprehensively and truly.
For innovative drug research phase I tolerance, need to have a strong ability of first aid emergency hospital, undertake project phase I clinical trial in the lab by full-time study doctors, nurses, nurse care experience is required) and related to the study drug professional high qualification for clinical doctors to participate. It is generally recommended to conduct a preliminary trial of 1-3 subjects in the department with the most guaranteed first-aid power in the hospital, such as the ward of the emergency care unit or the ward of the medical care unit, because in a small sample trial, the researcher and the hospital will have enough resources to implement rescue treatment for various clinical emergencies. When the pre-test results show that the safety is good and the process is controllable, the formal test to expand the sample size will be carried out. Through the pre-test of small sample, the safety situation and related characteristics of this drug in human body can be objectively and comprehensively known, and scientific data support can be provided for the implementation of large sample study and the formulation of emergency plan, which can effectively control risks and ensure the safety of subjects.
During the course of the trial, the investigator should pay attention to each abnormal indicator and any principal complaint of the subject. Researchers should closely monitor the changes of the indicators and focus on subjects, according to the abnormal situation timely adjust the treatment plan making body, until returned to normal or outcome, and combined with the subjects of clinical manifestation, laboratory examination indexes of anomaly and outcome information such as the careful to evaluate the safety of the drug, only after full assessment confirmed that security research into the next dose groups. In the event of trial-related damage, subjects will receive treatment and appropriate compensation. In addition to completing medical treatment, the investigator should also actively assist the subject to contact the sponsor and/or the insurance company and complete the relevant compensation settlement. The sponsor shall procure relevant insurance for the clinical trial to protect the rights and interests of the subjects.
3. Effectively improve the informed content, pay attention to the informed consent process, and ensure that subjects fully know the information
The informed consent should be written in simple and easy to understand words, avoiding the use of technical terms as much as possible, so that the subject is truly "informed". In addition, after hearing the researcher's instructions and reading the informed consent, the subjects can ask the researcher any questions related to the study, and the researcher is obligated to make detailed explanations one by one.
Objective indicators were used to assess subjects' knowledge of the clinical trial. For information on how to evaluate whether the subjects that informed consent, the author in the phase I clinical trials in the laboratory for assessment, the content of the informed consent form design questionnaire for testing purpose, process, matters needing attention of 10 aspects, such as the problem of random question 5, if the witting rate > 80% rating for the subjects already know relevant information, if the witting rate < 80%, the researchers will explain again, and the subjects should be the time to think.
In the ethical review, it should be noted that the informed consent should not contain any language that causes the subject to waive legal rights, nor should it contain any language that absolves the sponsor or the researcher of negligence.
For phase I clinical trial, participants tend to be 18 to 40 healthy subjects, both in the stage of childbearing age, and may have to start a family, so the sponsor and researchers should be based on previous findings in drugs, fully evaluate the effects of drug on the fetus, told the subjects to test how long can after pregnancy, and clear description in the informed consent.
4. Pay attention to the use of fake documents and security risks
Clinical trials of drugs require subject screening. To verify the personal information of healthy subjects, the doctors involved in the study asked to see the subjects' id CARDS. But at present, in the actual operation of this process, the use of false IDENTITY CARDS repeatedly occurred.
The common reasons for the use of false documents are as follows: A. Subject A knows from the recruitment information that the age requirement of this test is 18-35 years old, but his actual age does not meet the requirements, so he USES false documents in order to meet the inclusion criteria. B. Qualified and healthy subject B who has passed the screening will not be able to participate due to temporary business. In order not to miss the opportunity to participate in the clinical study, Subject B asked his friend C to take B's ID card and participate instead.
Obviously, if the actual age of the subject does not conform to the requirements of the study protocol, or if the subject impostors, it will cause a certain deviation of the results of the study, which will affect the quality of the clinical study of the drug and cause loss.
Imagine a biological equivalent test, each subject in two cycle test drugs respectively 2 and 2 controlled drugs, one subjects in the completion of the first cycle test because of personal affairs especially method to the next cycle of clinical trials, but because don't want to loss of nutrition allowance, so please his friends took part in the clinical trials of the second cycle, on the one hand, it may affect the clinical trial data, equivalent to the drug evaluation will bring great influence; On the other hand, if Subject C has not been examined and is a patient or carrier of an infectious disease, then other subjects in direct or indirect contact with subject C and researchers (including doctors, nurses and analytical testers) will be exposed to potential biohazard risk. Taking the new drug at the experimental stage may also cause unknown adverse effects on subject C's condition.
Therefore, the phase I clinical trial laboratory and researchers must keep a close watch to ensure the authenticity and accuracy of all data, and inform the subjects of the significance of the clinical trial and the importance of authenticity and reliability of data. To this end, the ETHICS Committee may draw the attention of the study doctors and study nurses to the review of the identity information of the subjects in the phase I clinical trial, and strictly check the relevant information during the screening period and each time the subjects are admitted to the ward during the trial to ensure the quality of the study.
In addition, it is called for the establishment of a networked subject database, similar to the current model in Japan, the United States and other countries, containing basic information, fingerprints, health information, participation in clinical trials, occurrence and evaluation of participants' participation in clinical trials. Fingerprints, a non-substitutable and non-counterfeit biometric number, are used to ensure the subject's true identity. Since 2010, our hospital has used the information management system for subject recruitment and screening of phase I clinical trials, which has achieved objective and comprehensive record and evaluation of subject trial information through electronic management. At present, the system has been promoted and used in three clinical trial institutions in Shanghai, realizing the subject information sharing of the three institutions, and effectively realizing the mastery of the subjects' participation in the trial. At the same time, in March 2016, our hospital also used the database management system for clinical study subjects in Beijing to connect with data from more than ten phase I clinical centers in Beijing, effectively managing the situation that subjects frequently participated in trials in Beijing and Shanghai. If it can be promoted to the phase I clinical trial institutions in Guangdong, Zhejiang, Jiangsu and even the whole China, it can effectively avoid the situation that subjects frequently participate in the phase I clinical trial in different institutions within a short period of time. The use of networked subject database is conducive to the unified management of subjects in a true sense.
5. Focus on social recognition of healthy subjects in the Phase I clinical trial
The development and progress of medicine cannot be separated from clinical research, and the research and development of new drugs cannot be separated from phase I clinical research. Without the participation and contribution of healthy subjects, how can a new drug benefit the majority of patients? In developed countries, open recruitment of drugs, the healthy volunteers of the phase I clinical trials is widespread, the subjects' contribution to the society has been the society generally agree that the government or relevant organizations have established clinical trial information and participants information database and management system, timely release information to the public to know the present situation of the research, judgment, and to choose whether or not to participate in research, timely access to the required treatment, but also promote the whole society awareness and recognition of clinical research. But due to historical reasons, in our society and the public for phase I clinical study of popularity is still very limited, the healthy volunteers to participate in phase I clinical trials for medical research in our country and the public health made irreplaceable contributions not only recognition, also tend to be mistaken for selling blood in disguised forms, and often by some irresponsible media contemptuously called "little mortar mouse body".