ICH in Focus: Six Months Post-E6(R2)—Reflecting on Practical Experience and Expectations vs. Reality

Dawn Myers

Dawn Myers, Director, Corporate Quality and Process Quality Management, INC Research/inVentiv Health.

Clinical Researcher—December 2017 (Volume 31, Issue 6)

Dawn Myers; Jill Collins

[DOI: 10.14524/CR-17-4046]

Following the initial adoption by the European Medicines Agency of the International Council for Harmonization’s (ICH’s) E6(R2) addendum to its Guideline for Good Clinical Practice (GCP) effective June 14, 2017, implementation continues to evolve. The areas of the addendum generating the greatest discussion within the industry include those related to Section 5.0 on Quality Management and Section 5.18.3 on Extent and Nature of Monitoring.

Although risk management is not new to the industry, Section 5.0 is new to GCP guidelines. It includes robust definition of a quality management system concept and detailed risk-based approach steps. Meanwhile, section 5.18.3 describes the varied approaches to monitoring that improve effectiveness and efficiency, in particular defining “centralized monitoring” for the first time and distinguishing it from both onsite monitoring and “clinical” monitoring (i.e., monitoring activities typically ascribed to the clinical research associate [CRA]).

Centralized monitoring allows for the near real-time review of accumulating trial data by an appropriately qualified and trained (cross-functional) team, which helps to identify missing or inconsistent data, examine trends, identify data errors, analyze sites and investigators, and/or select sites for targeted onsite monitoring. As such, the expectations for implementation may seem daunting and complex. Reflecting on the first six months post adoption, this column will examine expectations and practical experiences.

Expectations of Difficulties in Implementation

At a recent industry roundtable hosted by Tufts University, CluePoints, and PricewaterhouseCoopers, senior executives from 34 large pharmaceutical companies reflected on the implementation of the addendum within their organizations. A majority of the speakers noted that their companies are still in the preliminary stages of processing the elements of the guidance and assessing operational implementation activities.1 This appears to be a reflection of the breadth and depth of the addendum changes, which may indicate some challenges with adoption.

In another report, only one-third of the respondents to a 2017 AVOCA pharmaceutical industry survey noted that gaining alignment on risk was “easy” from an internal perspective, and even fewer indicated it was “easy” to gain alignment externally.2 Additionally, outsourcing continues to be a key solution in running clinical trials, as noted in the Nice Insight Industry Survey, with 75% of the respondents indicating that they outsource services or operations to contract research organizations (CROs) (36%) or to both CROs and contract development and manufacturing organizations (CDMOs/CMOs) (39%).3

Learning Opportunities

Given that the addendum has provided plenty of content to be digested and assimilated within companies, and requires alignment internally and externally with heavily outsourced clinical trials, what has been learned from practical experiences in these early days of implementation?

A key theme emerging is the importance of the cultural changes that are needed to change the way risks are identified and managed in clinical research.1 At the recent 8th Clinical Quality Oversight Forum, the attendees indicated in a live poll that “to drive a quality culture, leadership and communication were pivotal to ensure a successful outcome.”4

Companies that adopt and use change management principles are able to maximize practical improvements to ease the adoption of the new regulations and guidance. Industry leaders recognize that cultural changes require focused efforts and targeted activities, such as with the reorganization of longstanding processes, which will take time and determination to change.1

Additionally, the importance of establishing effective communications and of formalizing and aligning processes and training resources are noted to be essential elements of change management.1,2 These activities may include:

  • Release organization-wide, phased communications to increase awareness and importance for the forthcoming changes. At regular intervals, release various role-specific communications to provide clarity and insight to cross-functional collaborations and the ways in which all resources contribute to making the implementation a success.
  • Implement enhancements to cross-functional quality risk management methodology within existing controlled documents incorporating the seven steps outlined in ICH E6(R2) Section 5.0.
  • Incorporate cross-functional process changes to support both centralized and onsite monitoring activities using a risk-proportionate strategy inclusive of appropriate documentation.
  • Deliver participant workshops across therapeutic and functional business lines. Workshops enable stakeholders to test the processes and to experience the value of collaborative discussions while developing the appropriate strategy.
  • Establish a network of subject matter experts to be the change agents supporting their key business areas.
  • Develop cross-functional, global, role-based training on the ICH E6(R2) revisions and process changes.
  • Develop quality improvement implementation surveys against both process and training delivery. Surveys of various stakeholders and resources allow companies to make real-time process improvements and to ensure efficiencies and overall comprehension of changes.
  • Expand operational and quality support to allow for assistance, guidance, and stage-gates to reinforce compliance in implementation.
  • Implement risk management covering the clinical trial lifecycle—from design of the protocol and operational strategy to ongoing evaluation and response to risks and issues.
  • Reimagine resources by defining new roles, evolving existing roles, and shifting responsibilities related to monitoring for emerging risks. Provide resources with comprehensive, responsibility assignment matrix–driven definitions and enhanced cross-functional matrixed support along with new training.
  • Establish a “lessons learned” mechanism to allow for adaptions and refinements.

More on Monitoring

Pharmaceutical companies are also recognizing the opportunities that are supported by Section 5.18.3, which is seen as a validation of the risk-based monitoring approach. This section recommends that companies consider varied approaches to monitoring to improve the effectiveness and efficiency of monitoring by choosing onsite monitoring, centralized monitoring, or a combination of the two.

In addition, the guidance may fuel an acceleration of the adoption of risk-based approaches leading to improvements in efficiencies, quality, and timelines. Interestingly, this aspect is one that is interpreted and implemented under varying models.1 Human subject safety and well-being and data integrity remain the focus of E6(R2), but the use of more effective processes concentrating on what is most important allows for increased efficiencies. This is a move away from treating all data and processes with the same significance by demonstrating through critical data and process evaluation which data are of most importance, and how best to review and monitor during the course of the trial.

This risk-proportionate approach allows the focus to be on the data and processes that are directly linked to subject safety, rights, and welfare as well as the key efficacy variables. In a recent survey conducted by INC Research/inVentiv Health at DIA Chicago 2017, 77% of the respondents confirmed they are implementing approaches to trials based on critical data, critical processes, and risks-to-quality factors.

In the industry, technologies are still being developed and fine-tuned, and this can contribute to a challenge with implementation. There is a need to leverage the technologies that are available and make the necessary integrations to be able to surface actionable data needed to make decisions in near real-time. In other words, companies need “systems to be aligned to integrate data and provide unified risk-based viewpoints.5

Technology solutions are the catalyst for centralized monitoring activities, and provide additional monitoring capabilities that can complement and sometimes reduce the extent and/or frequency of onsite monitoring. As we move to using these new and improved technologies, we also must address how these electronic systems should be validated, backed up, and safeguarded. Provisions must be made for set up, installation, and use, along with validation and functionality testing, system security, maintenance, recovery, contingency planning, and decommissioning—all of which need to be appropriately documented.


In summary, upon the release of the ICH GCP E6(R2) amendment, companies may have developed some initial expectations related to the significance of the changes, but we are learning that companies are already taking on the changes through thoughtful cultural alignment and change management strategies. The acclimation to the guidelines is ongoing, however, and we must await the emergence of truly tangible impacts over time.


  1. Hughes P. 2017. ICH E6 R2: Talking big pharma’s response to the addendum. www.clinicalinformaticsnews.com/2017/10/20/ich-e6-r2-talking-big-pharmas-response-to-the-addendum.aspx
  2. Burrows A. 2017. Implementing the ICH E6 R2 guidelines and operational risk based approaches oversight. https://knect365.com/clinical-trials-innovation/article/32536b96-c36e-4f5b-91a3-397a38340a29/implementing-ich-e6-r2-risk-based-approaches
  3. American Pharmaceutical Review. 2016. Another exciting year for clinical research outsourcing. www.americanpharmaceuticalreview.com/Featured-Articles/183037-Another-Exciting-Year-for-Clinical-Research-Outsourcing/
  4. Bernie G. 2017. What drives clinical trial quality today? https://www.veristat.com/blog/what-drives-clinical-trial-quality-today
  5. Whittaker S, et al. 2017. ICH E6 R2 – Guidance and road map of tools for navigating the regulatory landscape. http://theavocagroup.com/news_events/ich-e6-r2-webinar/

Dawn Myers is Director, Corporate Quality and Process Quality Management, INC Research/inVentiv Health.

Jill Collins is Executive Director, Global Operations Management, INC Research/inVentiv Health.