Good Clinical Practice: Definition and Historical Background

Good clinical practice (GCP) is an international ethical standard guidance for designing, conducting, auditing, and reporting quality clinical trials. Note that clinical trials are defined as studies intended to discover new treatments or explore adverse reactions of novel investigation products in human subjects. Since clinical studies involve the participation of human beings, compliance with the GCP standards is crucial to ensure the safety, well-being, and confidentiality of all trial subjects.

While the GCP guidelines were finalized in 1996, the standards were enforced worldwide a decade later. Note that GCP was initially introduced by the International Conference for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), whose aim is to bring experts across Europe, the US, and Japan together (Vijayananthan & Nawawi, 2008). The history behind the formation of the guidelines is regrettable: disastrous events, such as World War II and the manufacturing of unsafe medications (e.g., maternal thalidomide), stressed the importance of voluntary consent of human subjects and drug safety testing. The Nuremberg Code, the Declaration of Helsinki, the Kefauver-Harris Amendments, the Belmont Report, and the International Guidelines for Biomedical Research Involving Human Subjects were the first milestones in the development of the GCP standards. Now the ICH-GCP is an essential factor in medical research.

The International Conference on Harmonization (ICH) for Good Clinical Practice (GCP) guidance has introduced strict rules and regulations for clinical trials. Medical experts are trying to implement an international standard for research (including design, performance, and report) in order to obtain valid and credible results. At the same time, professionals need to make sure that research procedures guarantee people’s safety and confidentiality.

Note that since 1996, ICH E6 has been accepted as the Gold Standard for International Good Clinical Practice. It has become the leading international quality standard for conducting clinical trials (Wilsher, 2015). ICH E6 guidance guarantees credibility, safety, and transparency of medical research.

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Good Clinical Practice: Principles and Usage

The E6 GCP Consolidated Guidance includes the following 13 principles:

  • 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).
  • 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.
  • The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.
  • The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.
  • Clinical trials should be scientifically sound and described in a clear, detailed protocol.
  • 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.
  • 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.
  • Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).
  • Freely given informed consent should be obtained from every subject prior to clinical trial participation.
  • All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification.
  • 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).
  • 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.
  • Systems with procedures that assure the quality of every aspect of the trial should be implemented.

In other words, the GCP principles state that established protocols and ethical principles are essential in research. Patients’ well-being and drug safety always come first. In addition, qualified personnel and good documentation practices are mandatory in clinical studies. Compliance with the ICH-GCP ensures people’s rights, data confidentiality, effective pharmaceutical marketing, and lower costs for both sponsors and patients.

3. Good Clinical Practice: Participants and Documentation

Although trial subjects are the focus of research, there are numerous participants whose roles and responsibilities are essential in clinical studies. From sponsors to ethical review boards, the following parties make clinical trials possible:

3.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)

The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) is the main institutional body that ensures the safety and well-being of trial subjects, especially those who are vulnerable and cannot give consent. Any IRB/IEC should consist of at least five qualified members. The names, roles, and qualifications of the IRB/IEC members should be stated clearly in accordance with the GCP standards.

Before the actual start of the clinical trial, the IRB/IEC must review the qualifications of the investigator and obtain mandatory documents, such as protocols, consent forms, information on payments, and data on the investigational products (Investigator’s Brochure). Consequently, the proposed study can be approved, rejected or modified.

The committee should also conduct an ongoing review of the trial after the actual start of the study. When concerns about procedures, drug safety, and subjects’ well-being arise, the IRB/IEC must notify the investigators shortly.

Note that meetings, functions, and written procedures are strictly regulated by the GCP guidance. All IRB/IEC records should be kept for at least three years after the termination of the trial and provided upon request.

3.2. Investigator

The investigator is the leading person responsible for conducting the clinical trial, and whose qualifications should meet the regulatory requirements. The investigator must be familiar with all procedures and investigational products. Consequently, the investigator must be able to communicate effectively with sponsors, IRB/IEC members, authorities, and even primary physicians.

Some of the main responsibilities of the investigator include; recruiting participants, utilizing resources, providing medical care to trial subjects, and following the protocols given by the sponsor and approved by the IRB/IEC. Note that a deviation of the protocol is allowed only in cases when the investigator has to eliminate immediate and logistic obstacles (e.g., replace a monitor), which should be documented subsequently. Also, appropriate documentation should be provided in case of an accidental unblinding.

The investigator and their staff are responsible for the investigational products, including delivery, storage, inventory, usage, and disposal, as well as documentation, such as labels, codes, and expiry dates.

As explained above, before the actual start of the study, the investigator must obtain IRB/IEC approval and consent forms (provided by the subjects, the subjects’ legally acceptable representatives or the impartial witnesses). Note that in nontherapeutic trials, it’s recommended to conduct research in subjects who personally give their consent. Also, it’s crucial to familiarize participants and representatives with aspects, such as the purpose of the trial, probabilities of random assignment, procedures, alternative treatments, responsibilities, expected benefits, possible risks, anticipated payments, trial periods, people to contact, protocols, and confidentiality.

Last but not least, the investigator is responsible for all the trial documentation, including progress records, financial aspects between parties, safety issues, premature termination, and final study reports.

The sponsor is responsible for quality assurance and quality control in compliance with standard operating procedures (SOPs). The sponsor is also responsible for facilitating communication and securing agreements between all the parties involved, across all trial-related sites, and during all stages of the study. Note that the sponsor may transfer their duties to a contract research organization (CRO), but they keep all the responsibility for the trial data.

The sponsor should also have qualified medical personnel to tackle various aspects of research, such as study design, data collection, documentation, and trial management. When it comes to data handling, the sponsor may employ an independent data monitoring committee (IDMC) to ensure safety and monitor progress. Digital data also requires special consideration. Electronic systems should be secure and reliable; they should allow data changes and audits without data deletion. Backup of original data and unambiguous subject identification codes are mandatory. Note that any transfer of ownership of the information collected should be reported to the relevant authority bodies. In case the sponsor terminates the development of a drug, they still need to keep the collected data records for at least two years.

Apart from data handling, one of the main responsibilities of the sponsor is to allocate clear duties and agree on crucial financial aspects, such as compensation of subjects. To set an example, the sponsor can select a qualified investigator or institutions for multicenter trials.

Also, the sponsor is responsible for the investigational product and its safety. Aspects, such as storage temperature, devices for product infusions, packaging, labeling, and supplying, are all handled by the sponsor. All changes and updates must be presented in the Investigator’s Brochure. Written procedures on handling, disposing, and returning of unused products are also required.

From multicenter trials to suspended studies, documentation (e.g., reports, forms, and digital files) should be updated before, during, and after the actual study. Before the start of the study, essential documents and IRB/IEC approval must be present. During the trial, the sponsor should report and document changes, adverse effects, compliance, and safety. In fact, the sponsor can appoint a monitor who can ensure patients’ safety and well-being. The monitor can act as one of the main lines of communication between the sponsor and the investigator, verify protocols, check data, report drop-out rates, determine adverse effects, and submit required documentation (e.g., trial-site visits). Sponsors can appoint an independent auditor as well. In case audits report serious noncompliance on behalf of the investigator, the sponsor can terminate the investigator’s participation. After the study, all relevant documents should be available and presented upon request.

3.4. Clinical Trial Protocol:

The clinical trial protocol is among the most important study documents. Usually, it includes general information (e.g., protocol title, names, and qualifications of staff), background information (e.g., description of the novel product and potential risks), trial aims, study design (including randomization, stopping rules, and codes), selection and treatment of subjects (mode of administration, follow-up periods, etc.), statistics (e.g., sample size), assessment of efficacy and safety, recordkeeping, information on insurance, publication policy, and ethics.

Note that the clinical trial protocol covers essential information, which is also required in the final study report.

3.5. Investigator’s Brochure

The Investigator’s Brochure is also mandatory. It includes clinical and nonclinical data that may be relevant in human subjects. It provides insights on dose, safety, modes of administration, and updated information. Usually, the sponsor must provide up-to-date information to the investigator and their personnel. The brochure must contain a title page and confidentiality statement. It also includes summary (e.g., physical, pharmacokinetic, and metabolic information), introduction (e.g., chemical formulas and indications), instructions for storage and handling, and any nonclinical information that may be relevant to human beings (e.g., species tested, duration of dosage, receptor binding, absorption, toxic effects, and mutagenicity).

Information can be confirmed by summaries of previous trials and experience during marketing (e.g., countries where the product has been approved or rejected). All information should be summarized, and data interpreted. Note that tables can support visualization and provide a better understanding of adverse effects, risks (e.g., overdose), and reactions.

3.6. Essential Documents:

Essential documents are those documents that allow the actual evaluation of the clinical trial. They demonstrate compliance with the GCP standards, facilitate monitoring, ensure data quality, and support auditing.

There are specific documents that apply before the trial, during the study, and after completion (or termination). The ICH-GCP guidance provides a complete list of the documents required (“Guidance for industry. E6 good clinical practice: Consolidated guidance”, 1996). Only after a final review of all investigator and sponsor files, a monitor can confirm a successful close-out of a clinical study.

Summary

The ICH-GCP guidance provides clear standards for designing, conducting, monitoring, and documenting clinical trials. As explained above, clinical trials are complex scientific and marketing endeavors, which involve the participation of numerous parties, products, and protocols.

Nevertheless, as trial subjects are the core of scientific progress, the Good Clinical Practice guidelines act as an international ethical standard guidance to ensure patients’ well-being and data confidentiality.

References

Guidance for industry. E6 good clinical practice: Consolidated guidance (1996). Retrieved from

https://catalyst.library.jhu.edu/catalog/bib_3466152

Vijayananthan, A., & Nawawi, O. (2008). The importance of Good Clinical Practice guidelines and its role in clinical trials. Biomedical Imaging and Intervention Journal, 4(1).

Glossary

Impartial witness – A person who’s independent of the trial and who attends the consent process when the subject or their legally acceptable representatives cannot read.

Investigation product – An active ingredient or placebo being studied or utilized as a reference in research.

Mutagenicity – Another term for genotoxicity or the destructive effect on a cell’s genetic material.

Nontherapeutic trials – Studies in which there is no expected direct clinical benefit to the participants.

Subjects’ legally acceptable representatives – An individual (or a juridical body) allowed to consent on behalf of the subject.

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