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What the New FDA Guidance for ICH GCP E6 R2 Means for Sponsors and CROs

FDA Guidance for Good Clinical Practice (GCP) is an international quality standard defined by the International Council for Harmonization (ICH) that governs ethical and scientific considerations for designing, conducting, recording and reporting trials involving human subjects. Compliance with FDA Guidance for GCP in clinical trials helps to assure that the rights, well-being and safety of trial participants are protected and that the data generated in the trial is credible.

Governments around the world utilize guidance documents from ICH to develop regulations around clinical trials. The first ICH-GCP guidance document (ICH E6: Good Clinical Practice: Consolidated guideline) was published in 1996, and served to provide a path forward for mutual acceptance of clinical trial data across regulatory agencies from many different countries.

An addendum to this original 1996 guidance has recently been published by the ICH in order to address advances in technology and other issues. On March 1st, 2018, the FDA adopted its version of this addendum, known as the E6(R2) Good Clinical Practice: Integrated Addendum to E6(R1). This FDA addendum guidance document is designed to support and improve clinical trial quality and efficiency, while maintaining human subject protection and the reliability of clinical trial results.

It is critically important that all FDA-regulated organizations involved in clinical research understand and implement the policy revisions detailed in this recent guidance to ensure regulatory compliance. In this blog, we will discuss the most important changes described in this new FDA addendum guidance document, as well as how these new responsibilities should be implemented by sponsors. The guidance states that “the sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf…,” so any sponsor responsibilities discussed in this blog will also apply to CROs.

Risk-Based Quality Management

The new guidance recommends that the sponsor implement a risk-based quality management (QM) system that covers all stages of clinical trials and focuses on trial activities essential to ensuring human subject protection and the reliability of trial results. Quality management for clinical trials, “includes the design of efficient clinical trial protocols, tools, and procedures for data collection and processing, as well as the collection of information that is essential to decision making.”

The guidance supports a quality-by-design approach to QM. Towards this end, clinical trial designs need to be supported by tools and processes that utilize real-life data and past experience to eliminate avoidable protocol amendments and study protocol requirements and procedures that would generate poor protocol compliance. Regarding data collection tools and processes, the guidance recommends moving away from paper-based CRFs and use of Electronic Data Capturing (EDC) systems. This recommendation flows from the need to use trial information in real time to make informed decisions.

The risk-based approach to QM should be applied to both quality control (QC) and quality assurance (QA) tasks. The idea of risk identification and prioritization is a common theme throughout the guidance document to ensure clinical activities are focused on the important clinical risks.

The risk-based approach defined in the guidance has seven key attributes:

  • Critical process and data identification
  • Risk identification
  • Risk evaluation
  • Risk control (mitigation actions)
  • Risk communication
  • Periodical risk review
  • Risk reporting

Risks are prioritized based on:

  • The likelihood that the risk could happen
  • The impact on the patient’s safety or rights, and data integrity
  • The extent to which the risk is detectable

This risk-based approach to QM requires continuous analysis and improvement of each quality management process at the sponsor’s organizational level, as well as that of the clinical trial.

The guidance document also identifies the role of comprehensive competency-based training and SOPs as key elements of any QM system. “The SOPs should cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning.” Additionally, the on-boarding of a team and the training on a system and process are defined as requirements.

Data Integrity and System Validation

The new guidance identifies data integrity as a cornerstone of GCP, and states that trial data systems must ensure data integrity, particularly with regard to technology changes and software updates. Whenever there is a change in the design, operations or set-up of a clinical trial, or in a supporting process or system, data integrity must be carefully assessed with an eye towards minimizing the risks.

When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should:

  • Perform computer system validation. The approach to validation of these systems should be based on a risk assessment that takes into consideration the intended use of the system, as well as the potential of the system to affect human subject safety and the reliability of clinical trial results.
  • Ensure integrity of the data and metadata. Ensuring data integrity should be a priority when making changes to computerized systems (e.g., software upgrades, migration of data, etc.).

Risk-Based Clinical Trial Monitoring

According to the new Addendum guidance, the sponsor should “develop a systematic, prioritized, risk-based approach to monitoring clinical trials…. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or, where justified, centralized monitoring. The sponsor should document the rationale for the chosen monitoring strategy.”

A risk-based approach to study monitoring requires that the sponsor develop and follow an optimized approach to study oversite that includes appropriate amounts of both on-site and centralized monitoring. While on-site monitoring is performed at the sites that are conducting the clinical trial, centralized monitoring is conducted remotely and can help reduce both the need and frequency for on-site monitoring. Centralized monitoring uses qualified data managers, biostatisticians, etc. to analyze collected data from the clinical trial in a timely fashion in order to help determine if the data is reliable.

The guidance recommends the use of statistical analysis on the data collected using centralized monitoring in order to “identify missing data, inconsistent data, data outliers, unexpected lack of variability and protocol deviations.” Any findings, decisions or corrective actions resulting from centralized monitoring should be documented and archived during the trial with an accessible audit trail.

Risk-based clinical trial monitoring depends on an effective risk-based QM program. The guidance calls for the development of a monitoring plan by the sponsor “that is tailored to the specific human subject protection and data integrity risks of the trial. The plan should describe the monitoring strategy, the monitoring responsibilities of all the parties involved, the various monitoring methods to be used, and the rationale for their use. The plan should also emphasize the monitoring of critical data and processes. Particular attention should be given to those aspects that are not routine clinical practice and that require additional training. The monitoring plan should reference the applicable policies and procedures.”

Finally, the guidance discusses the importance of timely reporting of the results from the trial monitoring program (both on-site and centralized) to the sponsor management team that is responsible for trial oversite. The results of the monitoring activities should reported with enough detail to allow the verification of compliance with the monitoring plan. Risk-based monitoring requires the data included in monitoring reports be aligned with the criticality of the monitored processes and data. Any compliance deviations identified in the reports, or corrective actions taken due to those deviations, need to be documented in a traceable way.

Recommended Changes for CROs and Sponsors

Based on this new Addendum guidance from the FDA, both sponsors and CROs should make the following adjustments in order to align with the guidance:

  • Adopt risk-based quality management for both QA and QC activities
  • Where necessary, adjust SOPs on clinical trial monitoring, data management, CRO oversight, etc. to reflect a risk-based QM and trial monitoring system.
  • Make sure all applicable personnel are trained in risk-based management strategies and, specifically, in your risk-based QM and trial monitoring systems.
  • Develop a centralized monitoring strategy for your clinical trials and clearly define when and how on-site monitoring will be used.
  • Make sure you have a reporting system in place to support a centralized monitoring strategy.
  • Make sure your monitoring reports are aligned with a risk-based approach to QM.
  • Develop a comprehensive risk-based clinical trial monitoring plan.
  • Maintain documentation on validated status of any computer system relevant to GxP, as well as any computerized system involved in clinical trial activities.
  • Establish a system for evaluating and documenting data integrity in all trial-related data systems.
  • Establish a CRO oversight strategy for any GxP activities carried out on behalf of the sponsor.


The new FDA GCP Addendum guidance document addresses some of the key points of clinical trial inefficiency and complexity: trial design, patient safety, data integrity and computer system validation, along with clinical trial design, management and oversight. This guidance document updates the standards for clinical trial quality management and monitoring to reflect common challenges and new technologies utilized in modern trials. With its focus on risk-based quality practices, the guidance has the potential to support improved efficiency and patient safety, better data quality and cost savings for clinical trials.

If you would like to discuss your plan to ensure data integrity and identify and validate relevant systems in your clinical trial, please feel free to contact us for a free, no obligations consultation.

About the Author

Dale Curtis Jr. is the President of Astrix Technology Group. For over 18 years, Mr. Curtis has built an impressive track record of leadership and success in delivering high quality technology and laboratory informatics solutions to scientific organizations involved in research, development, quality and manufacturing. He has a proven talent for helping these organizations deploy innovative solutions that provide a step change in business intelligence, turn data into knowledge, increase organizational and operational efficiency, improve quality and facilitate regulatory compliance.