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ICH E6 Amendment Emphasizes Risk Based Approaches in Clinical Trials

July 2017


The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Efficacy Guideline for Good Clinical Practice [ICH E6 GCP (R1)] became effective in May of 1996 and “describes the responsibilities and expectations of all participants in the conduct of clinical trials, including investigators, monitors, sponsors and IRBs.” This Guideline provides details on how to properly manage a clinical research trial along with the requirements of the trial master file. Documentation requirements were outlined, but the methodologies to accomplish these requirements were not initially included, as it was generally left to the discretion of the organization to determine how to implement the applicable processes.

In November 2016, ICH E6 was amended to reflect current industry needs and practices. The ICH E6 (R2) Introduction section states:

Since the development of the ICH GCP Guideline, the scale, complexity, and cost of clinical trials have increased. Evolutions in technology and risk management processes offer new opportunities to increase efficiency and focus on relevant activities. When the original ICH E6(R1) text was prepared, clinical trials were performed in a largely paper-based process. Advances in use of electronic data recording and reporting facilitate implementation of other approaches.1

The risk management processes included in the recent addendum focus on oversight activities and quality management of the clinical trial. Risk based approaches are not new to drug development; they have been used for years in medical device development, as well as in validating computer systems.

There is no “out of the box” solution to implementing a risk based monitoring program and quality management system. In developing these programs, the sponsor should include applicable stakeholders, take into consideration associated risks for each phase of a clinical trial, and coordinate the responsibilities of managing identified risks. Managing risk is a continuous process and should start at a sponsor’s program level, disseminating down to the protocol level.

Risk Based Monitoring

The concept of using a risk based monitoring approach for clinical trials has been around for a few years. In 2013, FDA provided a Guidance for Industry Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring. In the guidance, FDA encourages sponsors to develop monitoring plans that manage important risks to human subjects and data quality and address the challenges of oversight, in part by taking advantage of the innovations in modern clinical trials. A risk-based approach to monitoring does not suggest less vigilance in oversight of clinical investigations. Rather, it focuses sponsor oversight activities on preventing or mitigating important and likely risks to data quality and to processes critical to human subject protection and trial integrity. Examples of these types of risks include but are not limited to the following: deviations related to inclusion and exclusion criteria, late reporting of SAEs, and temperature or humidity excursions related to the investigational product or samples. Furthermore, FDA recommends a quality risk management approach to clinical trials and is considering the need for additional guidance describing this approach.2  

As stated in ICH E6 (R2), Section 15.8.3, “The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. (…) A combination of onsite and centralized monitoring activities may be appropriate. The sponsor should document the rationale for the chosen monitoring strategy.”

In accordance with this, any risk based monitoring strategy should be tailored to the needs of the trial and based on the best available information. If the strategy is developed and implemented by a Contract Research Organization(CRO), it is still the responsibility of the sponsor to ensure proper oversight of the trial that is being performed. Having a risk-based monitoring plan established before the study starts, and analyzing the data periodically for risk indicators and thresholds, will help move beyond a reactive sponsor oversight approach to a more proactive strategy. Whatever strategy is developed, it is important that it is adequately documented and focused on patient safety and ensuring reliable trial data. The strategy may include a combination of on-site, remote, and centralized monitoring.

Risk Based Quality Management System

The direction of using a risk based quality management system is relatively new to clinical trial management and oversight. ICH E6 (R2) introduces in Section 5.0, Quality Management, the idea that the sponsor should “implement a system to manage quality throughout all stages of the trial process.” The intent is to start at the time of protocol design to minimize potential harm as well as to promote efficient clinical trial conduct by focusing oversight on the most important aspects of study conduct and reporting.

Risk management is based on the best available information one has at that time. Ensuring human subject protection and the reliability of trial results are the two key areas to target in a risk based approach to overall quality. Using the RBQM (risk based quality management) process, an organization can assess protocols prior to study start. Understanding the major risks within a new protocol prior to launch will help an organization properly plan a clinical trial and reduce potential risks before they become a problem.

Other statements from ICH E6 (R2) that addresses the role of the Sponsor in quality management are:

  • To focus on trial activities essential to ensuring human subject protection and the reliability of trial results
  • To include the design of efficient clinical trial protocols and tools and procedures for data collection and processing
  • To ensure that the quality control methods used for the trial are proportionate to the risks inherent in the trial

As with most guidances and regulations, ICH E6 (R2) does not provide organizations with a “how to” on the implementation of a RBQM system. However, it does provide a brief outline of an approach to implementation. The approach includes the following steps:

  • Critical process and data identification - Identify the vital few processes and critical data that are essential to the trial objectives.
  • Risk identification - Identify risks to the key trial processes and data (consider both the system and protocol level). What might go wrong?
  • Risk evaluation - Risks should be evaluated based on likelihood, impact, and detectability.
  • Risk control - Decide which risks to reduce and/or which risks to accept.
  • Risk communication - Communicate to stakeholders what the risks are and how they are being controlled.
  • Risk review - Periodically review risk control measures to determine if the implemented measures are effective and relevant.
  • Risk reporting - Describe the quality management approach implemented in the clinical trial and summarize in the clinical study report.

Transferring Risk Management Activities

It is worth noting that the sponsor can transfer risk management to other parties. However, the sponsor is still ultimately responsible for all of the sponsor’s trial-related duties. If transferred, the process should be clearly documented. As specified by ICH E6 (R2):

  • [5.2.1] A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The CRO should implement quality assurance and quality control.
  • [5.2.2] Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in writing. The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf, including trial-related duties and functions that are subcontracted to another party by the sponsor’s contracted CRO(s).

Building quality into the design and operation of clinical trials, as well as continuously managing risk in a systematic manner, allows the Sponsor or designee to use limited resources to address the most important issues and priorities of each clinical trial. The point is to avoid the use of overly complex processes and tools to manage risk.


In summary, ICH E6 (R2) sets a more modern quality standard for clinical study processes through the recognition of different risks introduced into clinical trials through the utilization of electronic systems. These more modern standards have the potential to simplify clinical monitoring by embracing an adaptive risk-based approach, all while emphasizing the importance of patient safety, patient rights, and data integrity. However, to successfully implement these changes, a shift to a more holistic approach to drug development and clinical trials, particularly with regard to quality and compliance, will be needed to ultimately achieve cost savings by means of better planning.



  1. Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2), 09 November 2016:
  2. Guidance for Industry Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring (Aug 2013):

About the Author

Dr. Susan Leister, TRI Director of Quality Assurance, has over 15 years of regulatory and quality management experience. She holds a Ph.D. in Organizational Management with a focus in Leadership, as well as an MBA and BS in Biochemistry and Molecular Biology. She also has American Society of Quality Certifications for Quality Auditor and Six Sigma Black Belt.






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