The Fundamentals of Clinical Research - P. Michael Dubinsky

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have resulted in a range of harmful effects to the safety and well‐being of humans. Individual countries established regulatory requirements for clinical research in the development of a product to prevent such harmful effects. However, due to the cost of redundancies in resources, time, and additional exposure of an unapproved product to human subjects, a single guideline was developed with consideration of the current good clinical practices (GCPs) of the European Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and the World Health Organization (WHO). The objective of ICH E6 (R2) Guideline for GCP is to provide a unified standard for the European Union (EU), Japan, and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions. (ICH E6(R2) Introduction; Section on Good Clinical Practice History; Section on Drug Development in the Regulatory Environment).

      In this chapter, we will define GCP and present a practical interpretation of the GCP principles.

      The objectives of this chapter are:

      1 Define GCP

      2 Describe GCP principles and present a practical interpretation of the principles

      GCP is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well‐being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible. (ICH E6(R2) Introduction).

      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

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