Current status and challenges of biological sample management in clinical trials
Abstract
With the rapid development of clinical trials, relevant medical research and molecular testing based on biological samples are closely related to the progress of clinical trials, making the role of biological samples in clinical trials more and more obvious. Its standardized supervision model is to carry out high-quality clinical trials. important prerequisite for testing. Although laws and regulations related to clinical trials are increasingly improving, a large number of adverse events related to biological samples still occur, which seriously affects the progress and results of clinical trials and is one of the important challenges currently faced. Therefore, it is urgent to strengthen the supervision of biological samples and improve the management of biological samples in current clinical trials.
Current status and existing problems of biological sample management in clinical trials
1.1 Management of biological samples in domestic clinical trials
The use of biological samples in clinical trials is divided into pharmacokinetics, pharmacodynamics, immunogenicity and detection of major efficacy indicators according to the research purpose. Normally, blood, urine and biochemical routine items should be tested in clinical trial institutions. Some new indicators involving diagnosis or safety evaluation must be sent to the central laboratory designated by the sponsor. The sponsor should explain it in detail in the research protocol and obtain the informed consent of the subjects and review by the ethics committee [9-10 ]. For biological samples in clinical trials, clinical trial institutions have established a management system and standard operating procedures (SOP) covering the entire life cycle of biological samples; the sponsor has developed a sample management manual based on the “Good Clinical Practice for Drug Clinical Trials” “Guiding Principles for the Management of Phase I Clinical Trials of Drugs”, “Technical Guiding Principles for Clinical Trials of In Vitro Diagnostic Reagents”, “International Ethical Guidelines for Research Involving Human Health” and other relevant policies and regulations as the basic reference [11-14], combined with clinical trial institutions and the sponsor’s basic information, covering all aspects of interaction between the institution and the testing unit, including pre-collection preparation, sample collection, sample processing, sample storage, sample transfer and other processes.
Before the clinical trial is officially launched, the institution and the sponsor need to sign a “Clinical Trial Agreement”, which clearly stipulates the type, quantity, testing content, testing location and destination of the remaining samples after the designated testing items are completed. According to the agreement, the two parties perform their respective responsibilities in the management of biological samples. The clinical trial institution is responsible for the compliance collection and transfer of samples within the institution, and the sponsor is responsible for the compliance testing of samples outside the institution; some studies require the transfer of biological samples. Clinical trial institutions need to send them to the central laboratory designated by the sponsor for unified testing. No central laboratory or sponsor has the right to conduct biological sample testing unrelated to the trial plan. If any of the sponsor, contract research organization (CRO), and third-party testing company involves foreign investment, it must be registered or approved in accordance with the requirements of the “Regulations of the People’s Republic of China on the Management of Human Genetic Resources”, and the sponsor and the clinical trial institution must sign a commitment. The letter promises that the utilization and management of human genetic resources will not exceed the scope of approval, and that samples will not be used in violation of regulations.
1.2 Management of biological samples in foreign clinical trials
Compared with China, the development of clinical trials in Europe and the United States started earlier, and the policies and regulations related to clinical trials are also relatively complete. Since the 1970s, the United States has successively formulated regulations on subject protection (21CFR50), ethics committee regulations (21CFR56), investigational new drug application regulations (21CFR312), revised the U.S. Food, Drug and Cosmetic Act, etc., covering It establishes a clinical trial legal system for responsible entities such as institutions, sponsors, researchers, and ethics committees [1518]. The sponsor must submit relevant materials to the U.S. Food and Drug Administration (FDA) and Institutional Review Boards (IRB) before conducting clinical trials, including relevant pre-clinical trial experimental data, research protocols, Cooperation agreements, ethical review approval documents, informed consent and other materials, all clinical trials must be reviewed by the FDA before they can be carried out [19]. During clinical trials, FDA inspectors will supervise domestic clinical trials conducted in the United States or in the European Union, mainly including whether the research institution has relevant qualifications and authorization, whether the research plan has been updated, whether the subject records are complete, true and readable, and informed consent Whether the document is signed and whether the data records are complete, etc., further action plans will be taken based on the inspection results [20]. The UK’s King’s Health Partners Clinical Trials Office has relatively detailed regulations on all aspects of the entire clinical trial, including clinical trial training and supervision, record archiving, informed consent, and sample management. The SOP (2021) document for clinical trial sample management formulated by this office stipulates: The sponsor is responsible for ensuring that the laboratory where samples are analyzed complies with the relevant provisions of Good Clinical Practice (GCP), and the managers of the laboratory It is necessary to ensure that its trial team is composed of personnel with relevant qualifications; when conducting clinical sample collection activities, it is necessary to have corresponding approval documents such as collection plans, participant information forms, participant written consent forms, etc.; important guidelines and processes related to sample management To be described in detail in a study protocol or laboratory manual, work instructions, assay protocol, or analysis plan; if documents outside the protocol are used, they must be prepared in accordance with the protocol (and any subsequent revisions) by the KHP-CTO (King’s Health Partners Clinical Trials Office), clinical research associates (CRA) (or representatives) review and approve by the laboratory director (or representative), agreed sample management documents must be in place before the clinical trial, if samples need to be transferred to other If a third-party laboratory performs storage or analysis, a contract must be signed before the sample is transferred; experimental records must be kept, including preparation records of buffers, standards and reagents required for the analysis method, parameters for equipment debugging, etc., so as to repeat the test results and ensure Appropriate use of reagents and equipment. In addition, the SOP document makes relevant provisions for the labeling, storage, traceability, transportation, and reproducibility of experimental results of clinical trial samples [21-22].
1.3 Problems
Comprehensive clinical trials at home and abroad, both of them attach great importance to the management of biological samples, such as sample collection, transportation, preprocessing, preservation, delivery, recovery and other aspects. Although a management plan has been formulated before conducting sample-related experiments, there are still some hidden dangers, mainly including: the boundaries of responsibilities for the supervision of biological samples in clinical trials are not clear enough, there are deviations in the knowledge and understanding of sample supervision by all parties, and there is no clear Responsible body; the Ethics Committee attaches great importance to the scientific and ethical review of clinical trial projects, but its review of institutional qualifications and management systems for sample management is weak. Material transfer agreements are usually merged into the main agreement, and relevant content involving biological sample management is not included. Ability to conduct independent reviews; throughout the clinical trial process, there is a lack of specialized departments to track and supervise the full-cycle activities of biological samples; problems with feedback and sharing of research results based on biological samples, especially feedback and sharing of data and results There is a lack of detailed guidance on the scope, method and extent; some clinical studies, especially those involving medical devices and those initiated by researchers, often ignore the scientific calculation of sample size and lack statistical support; blood samples and blood samples are not collected according to the requirements of the research protocol Solve problems such as operating time exceeding the window, refrigerator overtemperature, and paper records of sample tests not being timely [23].
Thoughts and suggestions on the management of biological samples in clinical trials
Biological samples are an important part of clinical trials. Strengthening the management of biological samples, improving the efficiency of use of biological samples, protecting the legitimate rights and interests of sample donors, and giving full play to the clinical research value of samples are important prerequisites for conducting high-quality clinical trials. All relevant institutions and units in clinical trials, when conducting relevant clinical trials, not only need to fully protect the legitimate rights and interests of sample donors, but also need to fully realize their respective protection and protection of samples when conducting a series of studies on the basis of following relevant policies and regulations. Supervision responsibilities, optimizing the sample supervision process, and raising awareness of sample resource sharing; in addition, actively explore the sharing form of test result data without damaging the interests of all parties, give full play to the value of biological samples, and promote the clinical application of research results. Transformation is a problem that we insiders need to focus on and solve.
