The Evolution of Good Clinical Practice (GCP): Past, Present, and Future Trends

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. It reduces exposure to investigational products, enhances data quality, accelerates new drug approvals, and lowers costs for sponsors and the public.

The evolution of GCP has been shaped by various factors, including ethical considerations, technological advancements, regulatory requirements, and a growing emphasis on patient safety and data integrity.

Historical Background:

 History of the GCP guidelines dates back to long ago. Understanding the background of the formation of ICH-GCP guidelines is crucial as it elucidates the reasons and necessity behind their creation.

1.    Hippocrates Oath (460 BC): It is a foundational document in medical ethics, outlining the ethical principles that physicians historically pledged to uphold.

 2.    Formulation of United States Food and Drug Act (1906 AD): It was the first federal law aimed at ensuring the safety and purity of food and drugs sold across the United States. The legislation required accurate labeling of ingredients on drug products and set the stage for subsequent regulations to safeguard public health and establish the U.S. Food and Drug Administration (FDA) as a regulatory authority overseeing the safety and efficacy of drugs in the nation.

3.    Nuremberg Code (1947 AD): The Nuremberg Code, developed in response to the unethical experiments conducted during World War II, laid the foundation for ethical principles in human experimentation. It emphasized voluntary consent and the need for scientific justification.

4.    Declaration of Human Rights (Dec 10, 1948 AD): The declaration was a response to the atrocities of World War II and aimed to establish a common standard for the fundamental rights and dignity of all individuals. In the context of medical experiments, the UDHR reinforced the importance of ethical considerations and the protection of human subjects.

5.    Kefauver-Harris Amendments (1962 AD): These amendments required the FDA to evaluate all new drugs for safety and efficacy before approval,; after a devastating Thalidomide tragedy occured in 10,000 infants over 20 countries.

 6.    Declaration of Helsinki (1964 AD): The World Medical Association’s Declaration of Helsinki introduced guidelines for medical researchers, emphasizing the importance of ethical considerations, informed consent, and scientific rigor in clinical trials.

7.    Formation of Belmont Report (1979 AD): This report formulated by National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, laid down foundational ethical principles for human subjects’ protection in research, emphasizing respect for persons, beneficence, and justice. The principles outlined in The Belmont Report played a key role in shaping international standards for ethical conduct in clinical trials, including the subsequent formulation of the ICH-GCP guidelines.

8.    International Guidelines for Biomedical Research Involving Human Subjects (1882 AD): The World Health Organization (WHO) and Council for International Organizations of Medical Sciences (CIOMS) released ‘International Guidelines for Biomedical Research Involving Human Subjects,’ consolidating global standards to help developing countries apply ethical principles in research, based on the Declaration of Helsinki and the Nuremberg Code.

 9.    ICH-GCP (1996 AD): The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) established guidelines to standardize GCP across regions (EU, Japan, and the US). ICH-GCP emphasized the importance of safety, data integrity, and risk management in clinical trials.

Present Status:

 In recent years, GCP guidelines have evolved to meet innovations in medical research. The 2013 ICH update incorporated electronic records and risk-based monitoring. The most-recent and widely used update was in 2016, where ICH released “E6 (R2) Good Clinical Practice: Integrated Addendum to ICH E6 (R1) ,” introducing updated requirements for risk-based monitoring, electronic records, and informed consent, aligning GCP standards with contemporary research needs.

These ICH updates to Good Clinical Practice (GCP) introduce a risk-based approach for quality management, shifting from sponsors’ micro-management of data to focus on crucial trial activities. Emphasizing Principal Investigator (PI) oversight, the guidelines address non-compliance, directing sponsors to perform root cause analyses and report serious breaches. Sponsor-CRO relationships are underscored, with sponsors maintaining oversight and documented approval for subcontracted services. In recognition of technological advancements, ICH incorporates electronic record-keeping standards, highlighting terms like ‘validation of computerized systems’ and stressing the importance of maintaining Standard Operating Procedures (SOPs) for data integrity during system updates or migrations.

Most recently, in June 2023, ICH E6 (R3) Guideline for Good Clinical Practice Guidelines draft was released for the stakeholders to comment. Unlike the recent guideline, it is unique on its kind and includes new updates in the glossary related to Computer System Validation and digitalization. Key changes involve the introduction of electronic Informed Consent, encouragement of quality by design and risk mitigation, and clarified Sponsor and Investigator responsibilities. Notable clarifications for Investigators cover source record identification, timely data review, and staff delegation. Essential records are categorized based on study characteristics. A significant addition is the concept of data governance, applicable to both Sponsors and Investigators.

In the current landscape of healthcare innovations, clinical trials are undergoing a transformative shift through technology integration. Electronic data capture (EDC), electronic health records (EHR), and wearable devices are pivotal in revolutionizing data collection and monitoring, enhancing the precision and efficiency of trials. The advent of risk-based monitoring (RBM) emphasizes resource allocation to high-risk areas, diverging from traditional on-site methods, thereby streamlining processes and cutting costs. Concurrently, patient-centric trials are gaining momentum, recognizing the crucial role of patient involvement in trial design for improved adherence, experience, and overall success. As clinical trials increasingly embrace a global scale, tapping into diverse patient populations, challenges arise in harmonizing regulations and navigating cultural considerations. This evolving landscape underscores the dynamic intersection of healthcare innovation and clinical trial methodologies.

Future prospects:

 Future prospects for Good Clinical Practice (GCP) are marked by transformative technologies. Real-world evidence integration from electronic health records and patient registries promises a broader understanding of interventions in practical settings. Decentralized and virtual trials, facilitated by telemedicine and wearables, aim to enhance diversity and reduce participant burden. Artificial intelligence and machine learning offer efficiency boosts in data analysis and decision-making within trials. Blockchain technology emerges for heightened data integrity and transparency. Adaptive trial designs, responsive to accumulating data, hold the potential for  enhanced efficiency and adaptability in evolving contexts. These innovations collectively shape the promising future of GCP.

 In conclusion, the evolution of GCP reflects a dynamic response to ethical concerns, scientific advancements, and the changing landscape of clinical research. The future trends in GCP are likely to be shaped by ongoing technological innovations, a focus on patient-centricity, and efforts to enhance the efficiency and reliability of clinical trials.

References: 

1.    Vijayananthan A, Nawawi O. The importance of Good Clinical Practice guidelines and its role in clinical trials. Biomed Imaging Interv J. 2008 Jan;4(1):e5. doi: 10.2349/biij.4.1.e5. Epub 2008 Jan 1. PMID: 21614316; PMCID: PMC3097692.

 2.    Otte A, Maier-Lenz H, Dierckx RA. Good clinical practice: historical background and key aspects. Nucl MedCommun. 2005 Jul;26(7):563-74. doi:10.1097/01.mnm.0000168408.03133.e3. PMID: 15942475.