Good Clinical Practice
Good Clinical Practice (GCP) is a set of internationally recognized ethical and scientific quality standards that must be followed when designing, conducting, recording, and reporting trials involving human subjects’ participation in clinical studies.
Every researcher intending to use human participants in their research must ensure that the study complies with regulations that protect the human subjects; the most commonly applied standards are those set forth as part of good clinical practice. GCP compliance assures the public and all groups involved in research involving human subjects that the rights, safety, and wellbeing of research subjects are protected and respected and ensures the integrity of the study’s data.
Any proposal relating to human subjects including healthy volunteers that cannot be considered as an element of accepted clinical management or public health practice and that involves either (i) physical or psychological intervention or observation, or (ii) collection, storage, and dissemination of information relating to individuals. This definition relates not only to planned trials involving human subjects but to research in which environmental factors are manipulated in a way that could incidentally expose individuals to undue risks.World Health Organization (WHO) Definition of Human Research
The principles of GCP are intended to apply to all clinical research involving human subjects related to pharmaceutical or other medical products. It also applies to other areas, including studies related to:
- Physiological, biochemical, or pathological processes and the response to physical, chemical, or psychological intervention
- Diagnostic, preventive, or therapeutic measures, designed to track response to these measures against a background of individual biological variation
- Determining the consequences of specific preventive or therapeutic measures for individuals and communities
- Identifying human health-related behavior in different circumstances and environments
- Employing either observation of physical, chemical, or psychological intervention
Six GCP Themes
- 1. Attention to detail
- 2. Documentation
- 3. Responsibility(-ies)
- 4. Risk and Risk Management
- 5. Quality
- Data and scientific
- 6. Validation, verification, and inspection
Let’s jump in and learn:
- Why is GCP Important?
- Good Clinical Practice Goals
- Foundations for Ethical Conduct in Clinical Research
- A Brief History of Good Clinical Practice
- The International Conference on Harmonization (ICH-GCP)
- Who Is Responsible for GCP Compliance?
- Good Clinical Practice Implementation
- Good Clinical Practice—A Win-Win Framework
Why is GCP Important?
The GCP addresses both the ethical and scientific integrity of clinical research involving human subjects to protect individuals and advance public health goals. It helps ensure that human participants in clinical research are not exposed to unnecessary risk and provides assurances that data generated from the study are valid and accurate.
Good Clinical Practice = Ethics + Quality Data
In their article, published in the Biomedical Imaging and Intervention Journal, Vijayananthan & Nawawi succinctly sum up why GCP is important. “GCP assures that the data and reported results are reliable and accurate and that the rights, integrity, and confidentiality of study subjects are respected and protected.”
Good Clinical Practice Goals
The goal of Good Clinical Practice is to apply the lessons of the past with regards to the importance of rules, regulations, and standards for conducting clinical testing on human subjects.
Good Clinical Practice goals are to provide standards and guidelines for the conduct of clinical research, including:
- Protecting human research subjects
- Subject safety
- Rights of subjects as related to research ethics, including:
- Right to be informed
- Right not to participate
- Right to withdraw at any time
- Right to protection of privacy
- Ensuring the quality and integrity of research data for regulatory decision-making, based on:
- A scientifically sound protocol that is designed to meet its stated objectives
- The quality conduct and oversight of the clinical study
- Assuring the existence and operation of quality systems
Foundations for Ethical Conduct in Clinical Research
The standards and guidelines set forth with GCP address requirements and include the foundation for ethical clinical research. Key considerations, for ethical conduct in clinical research, according to GCP, are as follows.
Scientific or Social Value
To justify exposing participants to the risk and burden of research, the answer to the question being posed in the clinical research should contribute to a scientific understanding of health or improve prevention, treatment, or caring for people with a given disease or disorder.
Before launching a study, the following need to be affirmed. This stops invalid and unethical research that wastes resources and unnecessarily exposes human subjects to risk.
- Are the research methods valid and feasible?
- Is the posed question answerable?
- Is the study designed with accepted principles, defined methods, and reliable practices?
Fair Subject Selection
Vulnerability, privilege, or other factors unrelated to the study should not be a consideration in recruiting participants for a study. Participants should only be selected based on the scientific goals of the study.
Also, anyone who is recruited for a study should be able to enjoy the benefits of the results. And, no group of participants (e.g., children, women, members of a minority group) should be excluded from a study without a scientific reason or heightened susceptibility to risk.
Favorable Risk-Benefit Ratio
Uncertainty, risks, and benefits—trivial or serious, long-term or transient—are inherently associated with a clinical research study. Thus, study leaders must weigh the potential benefits against the risks and determine if the potential downside is worth the upside results of the study.
An independent review panel should examine the study proposal to ensure that it meets ethics criteria and does not have conflicts of interest. The panel will also monitor a study through its duration. Among the questions that the independent review panel might ask are:
- Are those conducting the study as free of bias as possible?
- Does the study have a favorable risk-benefit ratio?
- Has the study been ethically designed?
- Is the study doing everything possible to protect research participants?
To ensure that potential participants willingly agree to participate and continue to participate in the research with a complete understanding of the potential risks, a process of informed consent must be followed. The process of informed consent confirms that the human subjects:
- Are accurately informed of and understand the purpose, methods, risks, benefits, and alternatives to the research.
- Make a voluntary decision to participate in the study.
- Understand how the study relates to them.
Respect for Potential and Enrolled Participants
Whether or not individuals decide to participate in a study or opt out of it, they should be treated respectfully in every interaction. This means:
- Keeping participants apprised of new information that might emerge in the course of research and could alter their willingness to participate in the study based on a change to the risk-benefit ratio
- Monitoring participants throughout the study and getting them the appropriate treatment for any adverse reactions or effects
- Removing participants who had unexpected effects from the study, but keeping them informed of the resulting research
- Respecting participants’ right to change their minds and to withdraw from the study without being penalized
- Respecting their privacy by keeping participants’ personal information confidential and protected
A Brief History of Good Clinical Practice
|460 BC||Oath of Hippocrates|
The Hippocratic Oath is one of the oldest binding documents in history. Its principles are held sacred by doctors. These include treating the sick to the best of one’s ability, preserving patient privacy, and teaching the secrets of medicine to the next generation.
|1938||U.S. Food, Drugs and Cosmetic Act|
Enacted by the Food and Drug Administration (FDA), this is the first time manufacturers were required to test drugs for safety and present the evidence of safety testing to the FDA before marketing.
Driven by the unethical experiments carried out at Nazi detention camps during World War, this code dictates that there should be a scientific basis for research on human subjects. It also calls for voluntary consent and the protection of participants.
|1948||Declaration of Human Rights|
The United Nations proclaimed and adopted this Declaration in response to the atrocities of World War II. This also reiterated the directives related to the treatment of human subjects in medical experiments that were set forth in the Nuremberg Code.
This was an amendment to the U.S. Food, Drugs, and Cosmetic Act of 1938 that was put forth in the wake of the Thalidomide tragedy. It mandated that the FDA would evaluate all new drugs for safety and efficacy before they are released to the public.
|1964 Revised 2000||Declaration of Helsinki|
Developed by the World Medical Association (WMA) and adopted by the WMA’s General Assembly, this declaration was meant to protect the rights of human subjects in medical research. It provides ethical guidance to physicians and other participants in medical research involving human subjects. In part, it says that “it is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the human subject.”
|1968||WHO Principles for Clinical Evaluation of DrugsThe WHO convened a scientific group and charged them with reviewing and formulating principles for the clinical evaluation of drug products. It applies to those new or already marketed and includes considerations for new indications or dosage forms for marketed products and new combination products.|
|1979||The Belmont Report|
Led by the National Commission for Protection of Human Subjects of Biomedical and Behavioral Research, the report defines basic ethical principles for conducting research that involves human subjects and sets forth guidelines to assure these principles are followed throughout the research process. The report included three key principles—respect for persons, beneficence, and justice.
|1982||International Guidelines for Biomedical Research Involving Human Subjects|
Issued by the WHO and the Council for International Organizations of Medical Sciences (CIOMS), “the Guidelines relate mainly to ethical justification and scientific validity of research; ethical review; informed consent; vulnerability of individuals, groups, communities, and populations; women as research subjects; equity regarding burdens and benefits; choice of control in clinical trials; confidentiality; compensation for injury; strengthening of national or local capacity for ethical review; and obligations of sponsors to provide health-care services.”
|1995||Guidelines for Good Clinical Practice (GCP) for Trials on Pharmaceutical Products Published by the WHO, this was meant to help developing countries apply the principles of the Declaration of Helsinki and the Nuremberg Code by consolidating the multiple guidelines into one universal guideline for global use.|
|1996||International Conference on Harmonization (ICH)’s Good Clinical Practice: Consolidated Guideline (ICH-GCP)This updated version of the 1995 GCP provides a consolidated standard that “protects the rights, safety, and welfare of human subjects, minimizes human exposure to investigational products, improves the quality of data, speeds up marketing of new drugs, and decreases the cost to sponsors and the public.” ICH-GCP was issued, in part, to overcome international inconsistencies with the application of GCP standards.|
|2001||International Standards Organization (ISO) 14155This standard established standards for clinical investigation of medical devices for human subjects, Part I and Part 2, clinical investigation plans (CIP). It provides requirements for the preparation of a CIP for the clinical investigation of medical devices.|
The International Conference on Harmonization (ICH-GCP)
The ICH was established in 1990 as a joint project to enhance the efficiency (through harmonization) of processes for developing and registering new medicinal products in Europe, Japan, and the United States while maintaining the regulatory requirements for safety and efficacy. The ICH brings together the regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of pharmaceuticals and develop guidelines. It strives to ensure that safe, effective, and high-quality pharmaceuticals are developed, registered, and maintained efficiently and following high ethical standards.
The International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines, or ICH-GCP, were created to protect the rights of human subjects who participate in clinical trials and to ensure scientific validity and credibility of the data collected in human clinical studies. Its objective is to provide a unified standard for the European Union (E.U.), Japan, and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.
The ICH-GCP guidelines were developed with consideration of the current good clinical practices 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 guidelines must be followed with studies that intend to generate clinical trial data intended to be submitted to regulatory authorities.
Good Clinical Practice comes from the regulations, guidelines, and standards that exist globally to govern clinical research. It has long been summarized using the thirteen principles of the International Conference on Harmonization (ICH).
- 1. Ethics
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).
- 2. Trial Risk vs. Trial Benefit
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.
- 3. Trial Participants
The rights, safety, and wellbeing of the trial subjects are the most important considerations and should prevail over the interests of science and society.
- 4. Information on the Medicinal Product
The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.
- 5. Good Quality Trials
Clinical trials should be scientifically sound and described in clear, detailed protocols.
- 6. Compliance with the Study Protocol
A trial should be conducted in compliance with the protocols that have received prior institutional review board (IRB) and independent ethics committee (IEC) assessments with an approval / favorable opinion.
- 7. Medical Care
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.
- 8. Trial Staff Qualification
Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).
- 9. Informed Consent
Freely given informed consent should be obtained from every subject prior to clinical trial participation.
- 10. Clinical Trial Data
All clinical trial information should be recorded, handled, and stored in a way that allows accurate reporting, interpretation, and verification.
- 11. Confidentiality
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).
- 12. Good Manufacturing Practice
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.
- 13. Quality Assurance
Systems with procedures that assure the quality of every aspect of the trial should be implemented.
The Declaration of Helsinki vs. ICH-GCP
The US FDA used to require that foreign clinical studies’ supporting applications for drug licensing comply with the Declaration of Helsinki. However, the FDA replaced the Declaration with the ICH-GCP. Among the reasons cited were:
- Need to assure the quality of foreign data submitted to the agency
- Desire to prevent confusion among researchers when the Declaration is revised
- Concern that further revisions could “contain provisions that are inconsistent with U.S. laws and regulations”
One concern with replacing the Declaration with ICH-GCP is that the Declaration has requirements that ICH-GCP lacks, such as:
- Investigators are required to disclose funding, sponsors, and other potential conflicts of interest to both research ethics committees and study participants.
- The study design has to be disclosed publicly in clinical trial registries.
- Research, notably that in developing countries, must benefit and be responsive to the health needs of populations in which it is done.
- It has restrictions related to the use of placebo controls in the approval process for new drugs and in research done in developing countries.
- It provides post-trial access to treatment.
- Authors are required to report results accurately, including publishing and making public negative findings.
Despite these differences, concerned parties across the world believe that ICH-GCP results in more acceptable data from clinical trials that are better suited for publication and submission to health authorities to support a new treatment.
Who Is Responsible for GCP Compliance?
The clinical study sponsor is responsible for ensuring that trials are conducted, and data are generated, documented, and reported in compliance with the protocol, GCP, and regulatory requirements. (A clinical trial sponsor is the individual, company, institution, or organization responsible for the initiation, management, and financing of a clinical trial.) GCP compliance enforcement also extends to investigators and site staff, contract research organizations (CROs), ethics committees, regulatory authorities, and research subjects.
Good Clinical Practice Implementation
Key activities involved in the proper conduct of a clinical trial instantiate global clinical practice implementation. These include the following:
- Define the trial protocols.
- Develop the standard operating procedures (SOPs) for the trial.
- Set up support systems and acquire the tools to facilitate the conduct of the study and collection of data in accordance with the protocol.
- Generate and secure approval for trial-related documents.
- Select trial sites and properly qualified, trained, and experienced investigators and study support staff.
- Establish an ethics committee to review and approve the protocol.
- Undergo review by regulatory authorities.
- Ensure compliance with Good Manufacturing Practice (GMP) to ensure the proper quality, handling, and accounting of investigational product(s).
- Conduct research in accordance with the approved protocols and applicable regulatory requirements.
- Perform site monitoring of a clinical trial to assure high-quality trial conduct.
- Manage trial data appropriately to assure that the data are complete, reliable, and processed correctly and that data integrity is preserved.
- Implement quality assurance processes to measure trial performance and data quality using systematic, independent audits.
- Share the results of the study in an integrated clinical study report containing clinical data and statistical descriptions, presentations, and analyses.
Good Clinical Practice—A Win-Win Framework
The importance of providing ethical guidance for clinical research should never be underestimated. Nearly all clinical studies come with an element of risk—some higher and more extreme than others. Good Clinical Practice provides the foundation and structural support that guides studies to ensure that the highest quality data is delivered with the utmost ethical treatment for human subjects.
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Last Updated: 6th November, 2021