How Small and Medium-Sized Businesses Can Capitalize on New ICH E6 Regulations


Applied Clinical Trials

Small and medium-sized businesses are seeking clarification on how the new ICH E6 guidelines will impact their business.

For the first time in over ten years, the publication of the ICH Guideline for Good Clinical Practice (E6 R2) in November 2016 put new regulations in the spotlight, making sponsors and CROs sit up and take note. The new guidelines account for over a decade of change, including new regulations, larger scale trials, higher costs, and greater complexity in trial planning and conduct. ICH E6 (R2) mandates a new set of requirements and an emphasis on clinical trial conduct to guarantee superior quality studies and outcomes.

These new regulations have started to have a significant influence on sponsors, CROs, software vendors, auditors, quality professionals, investigators and clinical trial sites themselves. Many small and medium-sized businesses (SMBs) are seeking clarification on how the guidelines will impact their business. The ICH E6 (R2) guidance specifies that the execution of Risk-Based Monitoring (RBM), and more specifically using Centralized Statistical Monitoring (CSM) as a core component of clinical trial execution, is recommended due to its ability to provide “additional monitoring capabilities that can complement and reduce the extent and/or frequency of on-site monitoring and help distinguish between reliable data and potentially unreliable data.”1 Both the regulators and Good Clinical Practice (GCP) are making RBM an essential, and GCP compliance concern as well.

The Society of Clinical Research Sites2 also stated that further confusion has arisen for trial sites themselves since “[RBM] is often defined to site personnel in different ways by sponsor and CRO representatives. As a result, site personnel are unclear what changes in monitoring tasks are related to [RBM], leading the term to become a catch-all for alternative monitoring practices. How these practices impact the site drives discussion linked to site leader perceptions about [RBM]”. For SMBs we need to try to consolidate some of the thoughts and expose some of the RBM myths.

Why should SMBs take note?

If it was difficult for large pharma to adopt a new approach it has been even more challenging for SMBs to find the best methodology. Since the introduction of the ICH E6 (R2) addendum, the industry has seen a rise in the implementation of a variety of RBM methodologies and technologies.3 However, quite often, SMBs are more reluctant to adopt such techniques as they perceive these types of approaches to be expensive, resource-intensive and complex. Consequently, they are generally unsure of the steps they need to take to implement an RBM strategy and the usual obstacle of inertia kicks in. This means that many SMBs are missing out on the huge value that the industry is starting to see in terms of reduced monitoring costs and improved data quality leading to more accurate and timely submissions.

Paper-based data collection and reporting has diminished (although, amazingly, not disappeared altogether) with the rise of new digital technologies, such as electronic data capture (EDC), electronic Clinical Outcome Assessments (eCOA) and Interactive Response Technologies (IRT). Having such a vast amount of digital data at our fingertips enables enhanced risk assessment processes to pave the way for new approaches and opportunities to make clinical trials more efficient and ensure the quality, accuracy, and integrity of clinical trial data both during and after study conduct. The challenge is making sure that the various data are consolidated and harmonized to allow comprehensive interrogation techniques to identify the areas of most critical risk. This element should not be underestimated as many organizations (large and small) have tried and failed to effectively produce an integrated and reproducible dataset of this nature. Sponsors and CROs alike should ensure that a robust approach is utilised for setting up a database that can be used time and again for analysis.

Achieve regulatory compliance through a risk-based approach

The ICH E6 (R2) guidance4 specifies that the execution of RBM, and, more specifically, the use of CSM as a core component of clinical trial execution, is recommended due to its ability to effectively isolate areas of risk in a timely manner and, in so doing, complement and reduce both the extent and frequency of on-site monitoring. Sponsors have already started to see millions of dollars of savings in each trial that uses an RBM (due to reduced monitoring efforts) and that is even before the value of better data quality is accounted for.5

Many SMBs are still unsure of how to embrace RBM and often how it might realize the significant value highlighted above. Rather than fearing the change, organizations should see this as an opportunity to embrace improved and more efficient approaches to trial design, conduct, oversight, recording, and reporting, while continuing to ensure human subject protection and the reliability of trial results. Seeking consultation on the ICH E6 (R2) addendum and RBM methodology can be a logical place to start. Partners can help organizations fundamentally understand what the regulation wants and how it might specifically affect their ongoing process and people. By demonstrating how a risk-based approach meets the compliance obligations, many SMBs will be reassured that they can implement an approach that not only achieves regulatory compliance but also improves both cost and resource efficiencies.

For SMBs to achieve compliance in RBM without the use of a partner there are a few steps to take:

  • Implement a quality assurance and risk assessment process that is reproducible across programs of studies

  • Ensure you understand what is expected of you in terms of risk planning, mitigation and oversight

  • Make sure everyone is clear of the additional responsibilities for sponsors, CRO and clinical trial sites and communicate these definitively across the various groups

  • Be bold and confident in establishing a monitoring plan that addresses only sites and patients that are truly at risk

However, if SMBs need additional guidance from partners to facilitate ICH E6 (R2) compliance then support packages and starter packs are available that are designed to guide SMBs from consultation about the regulations themselves, pre-study risk assessment and risk mitigation techniques used from study-start through to database lock and submission. The key is to find an approach that offers both consultation services and technological software that addresses the challenges faced by small and mid-sized research organizations in effectively adopting RBM and ensuring compliance with ICH E6 (R2). People, process and technology are all affected but there has rarely been a better opportunity since compliance with the regulations will yield better outcomes at lower cost.

Can SMBs fast-track their ICH E6 (R2) compliance?

SMBs should review their current approach in terms of clinical trial planning and execution to fast-track their ICH E6 (R2) compliance and RBM adoption. Guidance from risk-based monitoring providers can help in the following ways:

· Develop an understanding of the ICH E6 (R2) guidelines and the fundamentals of RBM methodology

· Establish an overview of the pre-study risk assessment & mitigation planning process

· Establish Key Risk Indicators (KRIs) specific to their study / therapy area – review their purpose, key considerations for optimal effectiveness and review a set of standard KRIs.

· Develop a comprehensive Data Quality Assessment (DQA) plan-this includes comprehensive statistical data monitoring as a key step in risk detection, evaluating what it comprises and its critical importance in surfacing risks in clinical and operational data that may not have been anticipated via pre-study risk planning.

As the industry changes and evolves, it will be essential for SMBs to learn how the regulations will impact them for the better, and to understand how an RBM approach can be implemented quickly and efficiently to suit their specific needs.


  2. Society for Clinical Research Sites. 2017. SCRS InFocus.
  3. An Updated Look at Risk Assessment and Risk-based Management Practices. MCC Industry Practices Insight Reports. Metrics Champion Consortium:
  5. Removing the ‘Risk’ in Risk-Based Monitoring: What We Have Learned in the Last 4 Years from the Practical Implementation of RBM. Taken from Pfizer’s presentation at CBI's RBM. 2017 Risk-Based Trial Management and Monitoring Conference in Philadelphia.


Patrick Hughes is Chief Commercial Officer for CluePoints.

He can be reached at, Information on their ICH E6 (R2) compliance and RBM adoption is here CluePoints Starter Pack.

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