Читать книгу The Fundamentals of Clinical Research - P. Michael Dubinsky - Страница 81

The Good Clinical Practice Guideline presents a set of principles which lay the foundation for the responsibilities and operational standards that are presented in the Guideline. We can think of the principles as those beliefs that will guide the behavior and chain of reasoning for all who are involved in the conception, planning, and execution of a clinical trial in order to protect human subjects and ensure the integrity of trial data.

There are 13 principles (ICH E6(R2) 2). Presented below are the principles and a practical interpretation of each principle to enhance understanding of the principle and facilitate its application in the conduct of clinical research.

1 2.1 Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s).This principle is stating that clinical trials will follow those principles concerned with the safety, rights, well‐being of research subjects and all other principles, guidelines, and regulations that are relevant to the conduct of clinical research.

2 2.2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks.Considerations for benefit‐risk to a trial subject and society occur before a trial is initiated as well as during the trial.Aside from the potential contribution to science and society, there is no guaranteed direct benefit to a volunteering clinical research subject in that,The researchers do not fully know if the investigational product will workWhile participating in a clinical trial, a subject will benefit from medical care for any adverse effects associated with their participation in the trial, but this benefit is their rightWhile participating in the clinical trial, a subject may undergo procedures that diagnose or monitor their disease condition more regularly than standard care but this is because they are receiving an investigational product for which the safety profile is unknown.The subject may receive monetary compensation for participating in the trial, but this compensation should not be in amounts to influence or coerce the subject into taking part in the trial.However, some information about the efficacy/effectiveness of the investigational product may be already known from previous clinical or nonclinical experience and this information could be used in the assessment of benefit.The assessment of risk to the subject may largely be attributed to:Known and unknown adverse effects of the investigational productThe burdens (e.g., adverse effects, physical, emotional, and mental) endured by the subject to undergo the study proceduresThe effects of the progressive course of the potentially untreated or under‐treated disease depending on the effectiveness of available alternative careThe chance for untreated or under‐treated disease depending on the effectiveness of available alternative care in a placebo – or other approved comparator – controlled trial,The overall benefit‐risk assessment will consider all the potential benefits and risks above (perhaps there are more). Given the limited known potential benefit, primarily, the known risk of the investigational product and the burden of study procedures will be weighed against the risk of the disease conditions and course to secondarily assess benefit‐risk of the clinical trial. The safety and efficacy data from the ongoing study and all other ongoing and completed relevant nonclinical and clinical trials will be collected and evaluated with other risk factors for the on‐going assessment of benefit‐risk for study subjects. (Chapter 18 The Clinical Trial Protocol and Amendments; Chapter 19 Informed Consent and Other Human Subject Protection; Chapter 21 Safety Monitoring and Reporting; Chapter 22 Monitoring Overview)

3 2.3 The rights, safety, and well‐being of the trial subjects are the most important considerations and should prevail over interests of science and society.This principle is essentially saying that the sponsor, investigator, IRB/EC and all of their representatives involved in the conduct of clinical research will first and foremost consider and prioritize the safety, rights, and well‐being of clinical research subjects above all other considerations for a clinical trial. Any considerations for regulatory, scientific, business, or other objectives are secondary. If there is a potential for harm to any research subject as a result of a decision to comply with regulatory (e.g., complying with requirements of the protocol), other scientific, or business objectives (e.g., saving time or money), the decision should be modified in order to protect the research subject even if it means unfavorable consequences for regulatory compliance (e.g., a protocol deviation), or scientific or business objectives (e.g., losing time or money). (Chapter 19 Informed Consent and Other Human Subject Protection; Chapter 21 Safety Monitoring and Reporting; Chapter 22 Monitoring Overview)

4 2.4 The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.Any clinical study design and the choice of and dosing regimen for the investigational product and controls must be justified by results from nonclinical testing and previous clinical testing of the investigational product, and what is known about the drug class of the investigational product. As additional trial data are accumulated from other trials during overall development of the investigational product, these data may be used to contribute to the supporting information. If a clinical trial protocol is amended for study design or if additional indications will be studied with the investigational product, then nonclinical and clinical information should also be supportive of the changes. (Chapter 18 The Clinical Trial Protocol and Amendments; Chapter 16 The Investigator's Brochure)

5 2.5 Clinical trials should be scientifically sound, and described in a clear, detailed protocol.A clinical trial design should have its basis on relevant scientific principles and methods and be clearly described in a clinical trial protocol, what we may refer to as the “standard operating procedure” for the experiment on human subjects. The instructions should be clear, comprehensive, and accurate. Regulatory authority(ies), IRB/IECs, investigators, trial managers, monitors, and other stakeholders of the protocol may identify deficiencies during review and implementation of the protocol. If at any time it is discovered and determined that the instructions are ambiguous or incorrect, then the protocol should be amended to ensure clarity and accuracy. The protocol should also be amended if it is determined at any time that the trial design is inadequate to meet the protocol's, scientific, GCP, and and/or business objectives for the study. (Chapter 18 The Clinical Trial Protocol and Amendments)

6 2.6 A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favorable opinion.A clinical trial protocol may be implemented only if it has the prior review and approval/favorable opinion of an IRB/IEC. If the protocol is amended, the procedures as described in the amendment may only be implemented if it has the prior review and approval/favorable opinion of an IRB/IEC. The conduct of the trial must comply with the approved protocol.In the real world, it is prudent for those involved in trial conduct to be attentive to approved versions of the protocol and to approved procedures before implementing those procedures. For example, a trial site may receive verbal notification from the IRB/IEC that a protocol/amendment has been approved, and with eagerness to enroll, may consent or administer a new procedure to a subject before receiving documentation of the approval. Upon receipt of the documentation of the IRB/IEC's approval, the date of approval was after the verbal notification and therefore the date of consent and new protocol procedure predated the approved protocol. The implementation of the protocol was therefore a violation of this principle and a violation of the effective protocol, if the scenario pertained to a protocol amendment.Another example where keen attention is needed to prevent noncompliance is that protocol compliance means EXACT compliance with the protocol procedures as described. For example, if vital signs in the schedule of assessments are at 08:00 with a grace period (“window”) of ±5 minutes, and the vital signs were documented as obtained at 08:07, then this is a deviation from the protocol. For an auditor or inspector, rare instances of these deviations may be “acceptable”; however, multiple instances may be classified as chronic noncompliance and warrant a significant audit finding. The sponsor should monitor and note all deviations from the protocol, evaluate the root cause, implement corrective action, and/or amend the protocol as needed to ensure compliance. (Chapter 21 Safety Monitoring and Reporting; Chapter 22 Monitoring Overview)

7 2.7 The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.Only physicians who are qualified by education, training, and experience may provide medical care or make medical decisions on behalf of subjects. These physicians will be qualified not only by general training, but by specialty training if applicable. The local regulations will also determine what qualifications a physician may have to perform certain types of procedures. For example, consideration should be given to the qualifications of the investigator for a trial that evaluates a contrast agent that is administered via infusion for radiographical imaging of liver lesions; i.e., whether the investigator needs to be a radiologist or a hepatologist. Additionally, a busy clinical site should ensure that an individual who is recording adverse effects as reported by a study subject is not inadvertently diagnosing or making decisions about the clinical severity and treatment of the adverse effects. (Chapter 21 Safety Monitoring and Reporting; Chapter 22 Monitoring Overview; Chapter 9 Investigator and Sponsor Roles and Responsibilities)

8 2.8 Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).Each individual, whether they are a sponsor, investigator, or IRB/IEC representative (employee or contractor) should have appropriate qualifications to perform their assigned tasks. The assignment of the tasks and the qualifications of each individual should be documented. There should also be documentation that the individual has been trained on the protocol‐specific procedure or function. Documentation may be in the form of charts of the organizational structure for a team, lists of assigned tasks, current curriculum vitae with copies of certifications as required, and general and protocol‐specific training records. If an individual changes roles during a trial or discontinues performing the trial task or function, the transfer and transition process of the responsibilities should also be documented. Consideration should also be given to conflicts of interest; e.g., someone with significant financial interest in the product or the trial site should not contribute to trial data. (Chapter 14 Trial Management; Start‐up, On‐Study, and Close‐Out; Chapter 15 Trial Resourcing and Outsourcing; Chapter 21 Safety Monitoring and Reporting; Chapter 22 Monitoring Overview)

9 2.9 Freely given informed consent should be obtained from every subject prior to clinical trial participation.Careful consideration should be given to how trial subjects are consented. It is important to note that consenting is a process and does not only mean the subject's signing of the consent documents. Freely given; i.e., voluntary, consent means that there is no coercion either via verbal, body, or written language or via other medium; e.g., power, financial incentive. The inclusion of vulnerable populations in a protocol should be justified. Sponsor, investigator, IRB/EC institutions may have policies against recruiting staff as research subjects for a trial as their choice to participate may be unduly influenced by their superiors. (Chapter 19 Informed Consent and Other Human Subject Protection)

10 2.10 All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification. This principle applies to all records referenced in this guideline, irrespective of the type of media used.The clinical trial protocol provides the instructions for study procedures and additional procedures for study conduct are prescribed via standard operating procedures (SOPs), GCP, and applicable regulatory requirements. During the trial, all evidence of trial conduct will be maintained as Essential Documents. At the end of the trial, study conduct and results are reported in a clinical study report. All documentation of trial conduct from study start‐up to study closeout will be documented as evident of trial conduct. The documentation should follow good documentation practices (be attributable, legible, contemporaneous, original, accurate, and complete), and be retrievable to retell the story of trial conduct as needed, during, immediately after, and several years after the ending of the trial. That trial data and information should be retrievable at any time is important to note: trial data and information should be maintained in a format, and storage formats should be updated as necessary, so that the data and information can be read or interpreted at any time in the future. (Chapter 29 Essential Documents; Chapter 21 Safety Monitoring and Reporting; Chapter 22 Monitoring Overview).

11 2.11 The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).The IRB/IEC, investigator, and sponsor have responsibilities to ensure the protection of information that may identify research subjects (e.g., name, contact information, initials) in order to respect their privacy. IRBs/IECs and local regulatory requirements may dictate which, if any, personal identification for subjects may be used in trial data and documentation and with whom their personal information may be shared. Investigators and sponsors will implement procedures to ensure that unauthorized subject personal identification are not released and shared intentionally or inadvertently. (Chapter 19 Informed Consent and Other Human Subject Protection; Chapter 21 Safety Monitoring and Reporting; Chapter 22 Monitoring Overview).

12 2.12 Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol.The sponsor will ensure that investigational products are manufactured, handled, and stored according to GMP. The sponsor will implement procedures for product handling, storage, and shipping from the distribution facility to investigators and for return, receipt, and destruction to the facility. The investigator will implement procedures for receipt, handling, storage, administration to subjects, and destruction or return of investigational product to the sponsor. The sponsor will also implement procedures to monitor the entire 'chain of custody' of the investigational products to ensure compliance with the protocol and applicable regulatory requirements. (Chapter 17 The Investigational Product (Clinical Supplies); Chapter 21 Safety Monitoring and Reporting; Chapter 22 Monitoring Overview).

13 2.13 Systems with procedures that assure the quality of every aspect of the trial should be implemented.All players, the IRB/IEC, investigator (and third parties), and sponsor (and CROs), will implement procedures that assure the quality of every aspect of the trial. Quality procedures include procedures for quality assurance and quality control, including establishing SOPs, training procedures, monitoring procedures, audit programs, ongoing quality control checks, and risk assessment and mitigation methods. (Source: ICH [1] Section on Quality in Clinical Trials).