Demystifying GCP and ISO 14155

Demystifying GCP and ISO 14155: Essential Quality Requirements for Clinical Trials

Clinical trials are the cornerstone of medical advancement, the critical bridge between laboratory discoveries and accessible patient treatments. They are complex undertakings, involving human participants, rigorous protocols, and vast amounts of data. Ensuring the safety, well-being, and rights of these participants, while simultaneously generating reliable and credible scientific data, is paramount. This is where Good Clinical Practice (GCP) and ISO 14155 come into play – two fundamental pillars ensuring ethical conduct and scientific quality in clinical investigations.

The Foundation: What is Good Clinical Practice (GCP)?

Good Clinical Practice (GCP) is not a single regulation but rather a set of internationally recognized ethical and scientific quality requirements. Its primary purpose is to ensure that clinical trials are designed, conducted, recorded, and reported according to strict ethical and scientific standards. The core principles of GCP were established by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) in their ICH E6 guideline.

The definition from the EU Directive 2001/20/EC, Article 1, Clause 2, succinctly captures its essence: "Good clinical practice is a set of internationally recognised ethical and scientific quality requirements which must be observed for designing, conducting, recording and reporting clinical trials that involve the participation of human subjects."

Key principles of ICH GCP include:

• Ethical Conduct: Clinical trials should be conducted in accordance with the ethical principles originating from the Declaration of Helsinki, ensuring respect for persons, beneficence, and justice.

   

• Risk-Benefit Assessment: Before a trial begins, the anticipated risks and inconveniences must be weighed against the anticipated benefit for the individual trial subject and society. A trial should only be initiated and continued if the anticipated benefits justify the risks.

   

• Subject Rights, Safety, and Well-being: The rights, safety, and well-being of trial subjects are the most important considerations and should prevail over interests of science and society.

   

• Obtaining Informed Consent: Freely given informed consent must be obtained from every subject before participation. This involves providing comprehensive information about the trial in a language and format the subject understands.

   

• Qualified Personnel: Clinical trials should be conducted by qualified individuals with appropriate education, training, and experience.

   

• Protocol Adherence: Trials must be conducted in compliance with a scientifically sound, detailed protocol.

   

• Data Integrity: All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification. Systems that assure the quality of every aspect of the trial should be implemented.

   

• Confidentiality: The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with regulatory requirements.

   

• Good Manufacturing Practice (GMP): Investigational products should be manufactured, handled, and stored in accordance with applicable Good Manufacturing Practice (GMP).

   

• Quality Assurance and Quality Control: Systems with procedures that assure the quality of every aspect of the trials should be implemented.

   

GCP provides a global ethical and scientific standard for designing, conducting, recording, and reporting trials that involve human participants. It is the fundamental framework ensuring that the data generated is reliable and that the rights and safety of participants are protected.

Focusing on Medical Devices: What is ISO 14155?

While GCP (specifically ICH E6) originated primarily from the pharmaceutical world, the need for similar rigorous standards for clinical investigations of medical devices became increasingly apparent. This led to the development of ISO 14155: Clinical investigation of medical devices for human subjects – Good clinical practice.

ISO 14155 is a specific standard that adapts the core principles of GCP to the unique context of medical device clinical investigations. It provides requirements for the design, conduct, recording, and reporting of clinical investigations to evaluate the safety and performance of medical devices for regulatory purposes.

Key aspects covered by ISO 14155 include:

• Ethical Considerations: Aligned with GCP, it emphasizes ethical principles, informed consent, and the protection of study subjects.

   

• Clinical Investigation Plan (CIP): Detailed requirements for the content and structure of the clinical investigation plan, which is equivalent to the protocol in pharmaceutical trials.

   

• Roles and Responsibilities: Clearly defines the responsibilities of the sponsor, principal investigator, and other parties involved.

   

• Clinical Investigation Conduct: Covers aspects like site selection, subject recruitment, data collection, monitoring, and handling of adverse events.

   

• Data Management: Requirements for data collection, recording, validation, and archiving.

   

• Reporting: Guidelines for interim and final reports of the clinical investigation.

   

• Medical Device Specifics: Addresses aspects unique to medical devices, such as the handling and accountability of the investigational device, usability evaluation, and performance assessment alongside safety.

   

ISO 14155 effectively translates the broad principles of GCP into practical requirements for medical device studies, taking into account the differences in product lifecycle, risk profiles, and evaluation methods compared to pharmaceuticals.

Why Are These Standards Crucial?

The importance of adhering to GCP and ISO 14155 cannot be overstated. They serve multiple critical functions:

1. Protection of Human Subjects: This is the most fundamental reason. These standards ensure that participants are fully informed, their rights are respected, and their safety and well-being are the top priority throughout the investigation. Without these standards, there would be a significant risk of exploiting vulnerable populations or causing undue harm.

    

   • Example: Ensuring the informed consent process is conducted thoroughly, allowing subjects ample time to ask questions and understand the risks and benefits before agreeing to participate.

      

   • Statistic: A study published in the New England Journal of Medicine in 2011 highlighted that inadequate informed consent processes remain a significant issue in some clinical trials, underscoring the continued need for strict adherence to GCP principles.

      

2. Ensuring Data Integrity and Reliability: Regulatory bodies and the scientific community need to trust the data generated from clinical trials. GCP and ISO 14155 provide the framework for meticulous data collection, accurate recording, verification, and reporting, minimizing errors and bias.

    

   • Example: Implementing source data verification, where data recorded in the Case Report Form (CRF) is checked against the original source documents (like patient medical records).

      

   • Statistic: According to a report by the FDA, data integrity issues are a common finding during clinical trial inspections, emphasizing the challenges and the necessity of robust QA/QC systems mandated by GCP/ISO 14155.

      

3. Regulatory Compliance: Adherence to GCP and ISO 14155 is often a legal requirement for submitting clinical data to regulatory authorities like the FDA in the United States, the European Medicines Agency (EMA) in Europe, or the Ministry of Health in Israel. Data from non-compliant trials may be rejected, delaying or preventing product approval.

    

   • Example: A sponsor submitting clinical data for a new medical device must demonstrate that the investigation was conducted in accordance with ISO 14155 to support their marketing application.

      

   • Statistic: Regulatory bodies conduct thousands of inspections of clinical trial sites and sponsors annually. Findings related to non-compliance with GCP or ISO 14155 can result in warning letters, study holds, or data rejection.

      

4. Scientific Validity: By ensuring trials are well-designed, properly executed, and data is reliable, these standards contribute to the scientific validity of the findings. This means that the conclusions drawn from the trial are trustworthy and can genuinely contribute to medical knowledge and patient care.

    

   • Example: Ensuring proper randomization and blinding procedures are followed to minimize bias in the study results.

      

How Do They Ensure Ethical and Scientific Quality?

GCP and ISO 14155 achieve their goals of ensuring ethical and scientific quality through a comprehensive set of requirements that cover the entire lifecycle of a clinical investigation:

• Ethical Review: Before a trial can even begin, the protocol, informed consent form, and other relevant documents must be reviewed and approved by an independent ethics committee (IRB/EC). This committee assesses the ethical acceptability of the trial, focusing on subject safety and rights.

   

• Detailed Protocols/CIPs: The requirement for a comprehensive protocol (GCP) or Clinical Investigation Plan (ISO 14155) ensures that the trial is scientifically sound and clearly defines the objectives, design, methodology, statistical considerations, and organization of the investigation. This minimizes ambiguity and ensures consistency.

   

• Investigator Qualifications: Both standards mandate that investigators are qualified by education, training, and experience to conduct the clinical investigation. This ensures that the medical care of subjects is appropriate and that the data collected is accurate.

   

• Monitoring: Sponsors are required to implement a monitoring system to oversee the conduct of the clinical investigation. Monitors act as a crucial link between the sponsor and the investigator, verifying that the trial is conducted according to the protocol, GCP/ISO 14155, and regulatory requirements, and that data is accurately recorded.

   

• Adverse Event Reporting: Strict procedures for the collection, documentation, and reporting of adverse events are in place to ensure that any potential risks to subjects are promptly identified, assessed, and reported to the sponsor, ethics committee, and regulatory authorities.

   

• Quality Management Systems: Implementing a robust Quality Management System (QMS) is essential. This involves establishing Standard Operating Procedures (SOPs) for all trial-related activities, conducting internal quality control checks, and performing quality assurance audits to ensure ongoing compliance and data quality.

   

Examples in Practice:

• Informed Consent: A key aspect is the process of obtaining informed consent. GCP and ISO 14155 require that the investigator (or a designated person) fully explains the trial to the potential subject, including its purpose, procedures, potential risks and benefits, alternatives, and the right to withdraw at any time without penalty. The subject must have sufficient time to consider the information and ask questions before signing the consent form. A violation of this principle could invalidate the subject's participation and the data collected.

   

• Device Accountability (ISO 14155): For medical device trials, ISO 14155 requires meticulous tracking of the investigational device. This includes documentation of receipt, usage by each subject, return or disposal, and any maintenance or calibration performed. This ensures that the device used in the study is the correct one and is functioning as intended, which is critical for evaluating its performance and safety.

   

• Source Data Verification: A monitor visiting a clinical site will compare the data entered into the electronic or paper Case Report Form (CRF) against the original source documents in the subject's medical chart. They will verify dates, values, and events to ensure accuracy and completeness, a direct application of data integrity principles from both standards.

   

Conclusion

Good Clinical Practice (GCP) and ISO 14155 are indispensable frameworks for anyone involved in clinical trials involving human subjects, particularly in the medical device and pharmaceutical industries. They are not merely bureaucratic hurdles but essential safeguards that protect the rights and well-being of participants and ensure the scientific integrity and reliability of clinical data.

Adherence to these standards is a legal and ethical imperative. By embracing the principles and requirements outlined in GCP and ISO 14155, researchers, sponsors, and regulatory bodies can collectively contribute to the ethical advancement of medical science, bringing safe and effective new treatments and devices to those who need them most, built on a foundation of trust and quality.