What You Need To Know About The New ICH GCP E6(R3) Draft Guidelines

By Life Science Connect Editorial Staff

On May 19, 2023, the ICH released a draft of its Harmonised Guideline Good Clinical Practice (GCP) E6(R3) with updated regulatory standards for planning, designing, conducting, recording, and reporting clinical trials. These new guidelines respond to the drug development industry’s innovations in clinical trial types and data sources. They update the previous E6(R2) document by including new trial types and data sources, offering flexibility in technology use, aligning with quality by design (QbD) principles, introducing a dynamic, risk-based approach to trial design, and creating a universal set of standards for clinical trial data.

Once implemented, these guidelines will apply to anyone conducting clinical trials, including investigators, monitors, sponsors, and institutional review boards (IRBs). The GCP recognizes that clinical trials are highly individual and contain unique characteristics and creates a flexible framework that can be adapted to fit each trial's particular methodologies while maintaining high-quality standards. Understanding these guidelines is critical to designing and executing successful clinical trials.

Core Principles Of ICH GCP

ICH recognizes that clinical trials are fundamental to developing new medicines or finding new uses for existing therapies. When trials are designed and conducted well, they empower healthcare professionals to make evidence-based recommendations to patients. However, poorly designed or executed trials can risk participants' safety and produce unreliable results. Frankly, flawed trials waste investigators' and participants' time and resources. The principles outlined in the GCP draft are designed to ensure quality and safety while allowing for flexibility in trial design.

For example, digital health technologies such as wearable devices provide new opportunities for researchers to gather participants’ data and may increase diversity in clinical trial participants by enabling broader participation. These new guidelines allow such technologies to be utilized when appropriate for individual trials. However, QbD implementation means looking at the feasibility of this type of data collection and ensuring that new technologies are manageable for participants. QbD principles identify the data and processes needed to safeguard trial quality and realistically assess risks that threaten data integrity and reliability of trial results. When trials are designed with QbD in mind, they are flexible, not unduly complex, and safe and reliable by following several core principles: ethics, scientific quality, risk management, data integrity, and regulatory compliance.

Ethics: Participant Safety Comes First

Participants' rights, safety, and well-being are the priority of any clinical trial, more important than the demands of science or society. Participant safety should be reviewed periodically as new information that could affect their health or well-being becomes available. Risks and inconveniences to the participants must be weighed against potential benefits. Trials should only be conducted if the anticipated benefits outweigh the risks. Also, clinical trials should be inclusive and representative of the drug’s targeted population when applicable.

Ethical considerations also guide who can determine and perform medical care during the trial. Only qualified doctors, dentists, and other healthcare professionals approved by regulatory bodies may determine the medical care given to participants. Care can be delivered by other qualified healthcare professionals, such as nurses, as long as they follow applicable regulatory requirements. In all cases, patient confidentiality is protected according to all relevant data and privacy protection laws.

Informed consent is equally crucial to clinical trial ethics. Participation must be voluntary, and patients or their legal representatives must formally consent to the trial. Investigators need to educate participants or their legal representatives on the trial’s risks and benefits so they can make informed decisions. The participants also need to understand the trial’s design, requirements, and what technology they may be required to use. Finally, the trial’s practices must be consistent with the Declaration of Helsinki, the International Ethical Guidelines for Biomedical Research Involving Human Subjects, and any other applicable regulatory requirements.

Scientific Quality: Sound Practices Create Success

The guidelines related to scientific quality cover all aspects of the clinical trial. Without sound practices and reliable data, clinical trials fail. They must be designed, conducted, recorded, and reported in ways that ensure the data generated are reliable and robust.

First, the trials should be based on robust and current scientific knowledge and grounded in nonclinical and clinical information that is adequate to support a trial with human subjects. Trial design should reflect the current state of knowledge and experience with the investigational drug, including the condition that will be treated, diagnosed, or prevented, the underlying biological mechanism of the therapeutic, and the population for which the drug is intended. While the trial is underway, investigators should continue monitoring and reviewing current scientific knowledge to determine if the trial needs modification.

Only authorized individuals can design and conduct clinical trials, and multiple experts are needed during the trial, such as physicians, scientists, ethicists, technology experts, trial coordinators, monitors, auditors, and statisticians. Any individual involved in the trial should have qualifications that match their responsibilities.

The trial's scientific and operational design must generate substantial, reliable data to be effective. Quality is judged according to how well participants are protected, the reliability of the results, and subsequent decisions based on them. Strategies should be implemented to avoid, detect, and address serious noncompliance with GCP, the trial protocol, and relevant regulatory requirements.

Risk Management: Anticipate The Unanticipated

The guidance related to risk management also prioritizes patients’ safety by requiring trials to minimize risk and maximize benefits to the subjects as much as possible. Execution of trials' processes, measures, and approaches should be proportionate to the inherent risks and importance of the data. Risks are defined as related to the rights, safety, and well-being of trial participants, as well as anything that undermines the reliability of the results. Mitigation should focus on risks outside of those accrued during standard medical care. Likewise, risks related to quality should be anticipated when possible, and investigators should make adjustments when unexpected problems arise during the trial.

Data Integrity: Begin With Design, End With Transparency

Data integrity begins with protocol design. A clear, concise, and feasible protocol protects participants and produces reliable data. The protocol must state its scientific objectives clearly and explicitly. Also, any additional plans or documents, such as a statistical analysis, data management, or monitoring plan, should be clear, concise, and operationally feasible.

Naturally, clinical trials must generate reliable, quality data to be successful. Additionally, they should produce a quantity of data sufficient to provide confidence in the results. Trials require tools that capture, manage, and analyze data, which must fit the specific needs of the clinical trial and its protocol. These tools must also factor in any risk to the participants and avoid unnecessary complexity in their procedures and data collection.

All trial processes must support its key objectives, including computerized data collection systems. Trials should use efficient, well-controlled means to manage records to preserve data integrity, provide traceability, protect patient privacy and personal information, and deliver accurate reporting, interpretation, and data verification. Records must be retained securely by sponsors and investigators for the required period and made available to regulatory authorities upon request. The drug development process also necessitates transparency, including registration on publicly available databases and posting the trial's results publicly.

Regulatory Compliance: Review And Manufacturing

Clinical trials should follow applicable regulatory requirements and undergo independent review by an institutional review board/independent ethics committee (IRB/IEC). Trials should comply with a protocol that receives prior approval from these organizations. Also, the IRB/IEC should periodically review the trial per applicable regulatory requirements.

The investigational products created for clinical trials must follow good manufacturing practice (GMP) standards and be stored, shipped, handled, and disposed of according to the product’s specifications and the trial protocol. Manufacturers should ensure that the product retains its quality after production.

The use of these products should follow the protocol and other relevant trial directives. Also, the product should be manufactured, labeled, and handled appropriately to the treatment and maintain binding when needed. Methods for handling and shipping the product need to safeguard its integrity.

Benefits Of Implementing The New Guidelines

Sponsors and companies can benefit from these guidelines in several ways. First, participants’ care and safety are paramount to the trial's success, and companies that utilize robust reporting mechanisms to address adverse events quickly avoid regulatory problems later. Second, companies can increase efficiency by creating a risk-based approach that prioritizes QbD. These guidelines aim to streamline processes and create more efficient trials that are less burdensome for companies and participants. Third, they can improve their data quality by ensuring their data is reliable, complete, and verifiable, thus enhancing the trial's credibility and chance of success.

Planning for regulatory compliance also streamlines the drug development process. The ICH GCP proposes to create universal standards for clinical trials that can be applied across regions and countries, leading to standardization and harmonization to facilitate worldwide drug development. Following these standards helps companies create more efficient trials with enhanced patient safety, improved data quality, and regulatory compliance, resulting in reliable, safe therapeutics for patients across the globe. The ICH is currently receiving public comments on these draft guidelines. Regional deadlines and instructions can be found on the ICH website.