Patrick Hughes

Over the last year, sponsors and CROs have embraced centralized monitoring and risk-based quality management (RBQM) in a bid to keep trials on track under extenuating pandemic circumstances. The shift may have been out of necessity initially, but the benefits–from accelerated development timelines to a higher likelihood of study success–have been obvious. Now, there is no putting the genie back in the bottle: RBQM and centralized monitoring are here to stay.

When the pandemic hit in early 2020, unnecessary face to face contacts, including clinic visits, were halted and regulatory bodies recommended fresh risk assessments for all ongoing studies. This shift framed the traditionally conservative sector in a new light. Suddenly, concepts such as remote and centralized monitoring along with the broader RBQM paradigm, which have long been lingering at the side lines of clinical trial management, were brought into sharp focus. As companies navigated the minefield of regulation and inherent risk, tailored assessment and decentralized data collection became essential. Meanwhile, their benefits, pandemic or no pandemic, became obvious.

RBQM, with its ability to quickly prove therapies are safe and effective, can dramatically accelerate the drug development pathway. It drives up data quality and allows early risk detection, both of which are crucial to supporting the pace of programs and making high efficacy treatments widely available in the shortest time possible.

As such, we are now seeing an industry-wide move towards this new way of working. In a recent poll taken from our webinars, out of 650 industry representatives, 56% said there were either already implementing RBQM or were about to start. A further 25% said it was already an integral part of how they run their trials. Overall, 81% are either implementing or have already fully adopted RBQM.

 and addressing the huge additional risks the pandemic introduced to clinical trials was a daunting task. Yet, organizations were unfazed and worked quickly to develop the tools and processes they needed to ensure their studies could continue safely and effectively. 

One CRO, a global leader in early phase clinical research services, for example, applied CluePoints’ complimentary COVID-19 package, which incorporated a SARS-CoV-2-specific Risk Assessment template, to more than 100 studies. They used the tool, which features relevant risk categories, associated considerations, and detailed Key Risk Indicators (KRIs), to define COVID risk and establish mitigation procedures. For them, and many other organizations like them, going through this process has demonstrated the value of proactive risk mitigation in protecting data integrity and maximizing the chances of trial success.

RBQM solutions provide a way of identifying, visualizing, managing, and documenting the risks that could impact the outcome of a clinical trial. The method has proved its worth during the pandemic, especially in the race to find a vaccine, where at least one sponsor organization utilized the approach to support the rapid development of their product.

Centralized risk monitoring software allowed the sponsor to interrogate data from more than 100 global sites in near-real time. Using a combination of KRIs, quality tolerance limits, and statistical data monitoring techniques, a central monitoring team was able to conduct twice-weekly risk review meetings with the study team. This allowed potential issues to be identified, investigated, and rectified before they even had a chance to affect data quality.

By focusing on speed, accuracy, and reliability, the sponsor was able to mitigate risk to both patient safety and data integrity. In doing so, they were able to lessen any potential delays to final approval submission at a crucial point in the global health crisis.

Across the sector, every effort is being made to achieve unprecedented progress with vaccine trials and COVID-19 treatments. Several leading CROs have selected RBQM solutions to ensure that no data quality stone is left unturned in this mission. Such platforms allow clinical trials to detect risks as early as possible, meaning corrective action can be taken in record time–and this is a benefit that far transcends the pandemic.

Developers and sponsors around the world are united in their aim to get life-changing new medicines to the people who need them as quickly as possible. And, as demonstrated above, RBQM helps organizations to do just that. In addition, robust RBQM solutions allow teams to access information centrally, collaborate on investigations, and document any mitigations or remedial actions. Not only does this result in a clean dataset, but it also creates a reliable audit trial for regulatory scrutiny.

Traditional site monitoring methods, such as source data verification (SDV), are quite simply unable to provide the same level assurance within such rigorous processes and rapid timelines.

Centralized monitoring is another pertinent area in the field of clinical trial management. Cloud-based centralized monitoring solutions allow sponsors to interrogate clinical and operational data in real-time, increasing efficiency, improving patient safety and reducing costs.

Since early 2020, on-site monitoring has not, in the main part, been possible, and central statistical monitoring has presented a proven alternative. Statistical algorithms that interrogate study data accurately and in an unsupervised manner help to identify risks early. This allows stakeholders to focus their attention on atypical sites, patients, regions
or countries.

It has proved extremely useful during the pandemic, but this approach, which regulators have long advocated, seems set to stay in a world where remote working has gone from a “nice-to-have” to imperative for business continuity. Fortunately, it is possible to eliminate or reduce on-site monitoring without significantly impacting trial oversight. Sponsors and CROs utilize a centralized monitoring platform that triggers site follow-up by web-based applications, phone, or email if risks are detected.

Last year was an opportunity to reflect on what matters most–and it is vital not to lose sight of what we can achieve when we work collaboratively. By seizing the moment, we can continue to aspire to even greater achievements.

It has been an extremely challenging time for clinical trial management, but it has also demonstrated the benefits of early risk identification. As such, COVID-19 accelerating the implementation of RBQM solutions. The approach allows study leaders to use the risk assessment process to first identify and then focus on the most critical data–the safety and endpoint data that matters most to each individual trial. It has proven invaluable in effectively managing studies to database lock with all the necessary assurances.

Clearly, the inability to physically visit sites has tremendously impacted onsite monitoring, and sponsors have increased their reliance on techniques such as centralized monitoring. In this respect, COVID-19 has accelerated a movement that has been simmering since the 2016 release of ICH E6 (R2) and has helped to drive change away from inefficient, legacy practices.

Organizations are now committing to adopting these data-driven approaches as their permanent operating practices in the future. Astellas, for example, has said it has no plans to revert to SDV transcription checking, which the company has said does not provide the same value as risk-based management.

The pandemic has demonstrated the value of modern clinical trial management, meaning it will undoubtedly ensure that the long-promised shift to risk-based methodologies will finally become reality.

Sponsors know that if they are to have any chance of seeing an increase in drug development pipeline activity, they must do more with less. Virtual trials, remote monitoring, wearables, and RBQM are all attractive ways of doing just that, but, up until now, adoption has been slow.

The pandemic has provided the catalyst the industry needed to take the risk-based bull by the horns. And in moving from theory to practice, it has proved the approach can accelerate development while protecting data integrity.

https://www.outsourcing-pharma.com/Article/2020/12/07/How-has-COVID-19-impacted-clinical-trial-data-collection

https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/guidance-medicine-developers-other-stakeholders-covid-19

https://globalforum.diaglobal.org/issue/september-2020/looking-to-the-future-with-rbqm/

https://www.centerwatch.com/articles/24898-remote-monitoring-wont-require-post-pandemic-re-monitoring-fda-says

 Chief Commercial Officer and Co-Founder, CluePoints

Articles

How it has taken a global pandemic to reinforce the intrinsic benefits.

Why Centralized Monitoring and RBQM are Here to Stay

Participant safety is the clinical trial sector’s top priority-and striving to achieve this laudable aim also makes for more agile, flexible, and efficient studies. That’s what we learned from a second executive roundtable discussion, hosted by the Tufts Center for the Study of Drug Development (CSDD), and supported via an educational grant from CluePoints and PricewaterhouseCoopers, on the progress the industry is making toward implementing the requirements of the ICH E6 (R2) addendum.

	When it was introduced in 2017, ICH E6 (R2) represented the biggest change to international clinical research in two decades. Developed as a response to the rising complexity of studies and the industry’s increasing reliance in electronic data management and reporting systems, the update sought to define good risk management in the modern trial environment. It states that clinical programs should implement risk assessment at both the trial and system levels and that metrics on clinical monitoring and data management should be captured in preparation for clinical study reports.

	Following the addendum’s publication, Tufts CSDD held the first roundtable on the updated guidance and found companies in the early stages of a big change. Kenneth Getz, former director of sponsored research and research associate professor at Tufts CSDD, who was recently promoted to research professor and deputy director, organized and facilitated the event with colleague Yaritza Peña, a research analyst at the center.

	“Two years ago, companies were in the early stages of interpreting the guidance to translate recommendations into tangible operating practices,” said Getz. “Roundtable participants indicated their initial focus was largely on risk-based monitoring (RBM). They were beginning to implement risk assessment procedures to identify which operating practices were most impacted. Although apprehensive about how the addendum would affect their current standard operating procedures (SOPs), the attendees had all agreed that the revised guidance was a step toward more agile, flexible, and efficient clinical trials,” he added.

	These latest discussions, held in Boston in April, found that the organizations had made significant progress on a granular level, and were now taking a more holistic view. A total of 41 participants from organizations including Alkermes, GlaxoSmithKline, Pfizer, Roche-Genentech, Sage Therapeutics, Takeda, the Metrics Champion Consortium (MCC), and FDA took part.

	After a panel discussion about ICH E6 (R2) compliance, the companies offered up their own examples before addressing the barriers and anticipated direction of travel. They found that rather than focusing simply on RBM, the industry has been working toward improving study efficiency overall, by taking a much broader view of risk-based approaches to study execution, or RBx.

	“Company mindset has progressed from 2017,” said Peña. “Since then, many organizations have incorporated a risk-based framework across end-to-end development processes. Companies are refining the quality management plans developed during the planning and execution stage, and using technology to drive pattern identification, machine learning, and study-specific analysis.”

	The discussions found that new regulations had compelled companies to move away from a clinical research associate (CRA)-centric, on-site visit model of monitoring to a data-driven, central statistical approach that improves data quality and contributes to overall trial success. Roundtable participants said that utilizing technological solutions had enabled a risk-based approach, informed by objective data integration, that supported the critical thinking vital to being able to make the right patient safety decision at the right time.

	Amanda Hayden, director of global clinical services at Alkermes, said the industry had experienced “significant maturation” with respect to its response to ICH E6 (R2). “While many companies may have approached the update by addressing each subpart separately, the reality is that many of the processes are interconnected. Advancing clinical processes in a holistic fashion and thinking of risk in all facets of study planning, execution, and analysis creates synergies and efficiencies, and allows for better use of time, resources, and study data.”

	Companies chalking up success in this area are those that have recognized the opportunity and have since worked to reorganize SOPs and pathways to allow for a portfolio, rather than a program-wide view. They are making significant investment in analytical capabilities that not only apply to RBM and oversight, but also to operational outcomes such as enrollment and protocol feasibility. Advanced data visualization, for example, can automatically detect trends and anomalies, and automated query management systems assist with the reconciliation of serious adverse events.

	Study optimization is a natural consequence of utilizing these metrics, which allow companies even more sophisticated ways to distinguish between reliable and potentially unreliable data, and to avoid unnecessary protocol complexity. These opportunities are only set to increase as analytical techniques, including machine learning, natural language processing, and other types of artificial intelligence  (AI) are put to use in the clinical trial space.

	Achieving this holistic approach isn’t without its challenges, and integrating ICH E6 (R2) concepts into study planning and implementation is proving difficult for some sponsors. “Part of the challenge depends on the creation of an efficient interface between a proactive quality planning process and a risk-based monitoring process,” said Getz. “Another daunting task is shifting company culture to adapt to the necessary changes to study processes when anticipating risk and performance issues.”

	Getz further explained: “Since risk management is not currently a core operational competency, employees require training and monitoring to understand concepts such as data quality vs. data integrity, site monitoring vs. trial monitoring, and data reliability vs. trial results reliability.”

	According to the panelists, the companies currently embracing the opportunities of RBx have fundamentally changed the way data are verified, reviewed, analyzed, and managed within their organizations. This has taken commitment from senior leadership and a wholesale change both in company structures and culture. Strategies employed have included robust change management training and the digital upskilling of staff. Clinical study teams, tasked with examining ICH E6 (R2) requirements to ensure the right data quality oversight tools are being used, have also been set up.

	Some industry players have developed teams of subject matter experts (SMEs) with the responsibility to ensure the updated guidance is implemented. These SMEs are able to take an overarching view of risk identification, reporting and evaluation, cross-functional sharing of risk, and the monitoring of risk control measures across studies and protocols.

	“This horizontal view that rises above separate protocols and sites to take in the bigger picture, is the key to realizing the potential of RBx,” said Hayden. “The main drivers in successfully implementing a risk-based approach to study execution is to consider the interconnected nature of risk identification and analysis throughout the entire lifecycle of the clinical program.”

	While many of the companies at the roundtable said the project had increased operating costs, they also said these were offset by the benefits in terms of risk mitigation and proactive decision-making. As clinical trials become ever more complex and fragmented, RBx systems can be used to continue to consolidate and streamline studies while allowing for strategic oversight. In fact, many of the roundtable companies said they believed they were better placed to drive effectiveness and optimize performance in the next three to five years.

 appeared best placed to leverage the rich data that will be generated by ever-advancing analytics. While AI utilization is still in its infant stages, for example, the roundtable participants expect it will soon play a role in efficiently identifying areas of risk and be able to guide stakeholders to the best possible solutions. They are also in the best position to respond to expected regulatory changes-FDA is currently looking at revisions for E8 as well as a proposal regarding the next iteration of E6, for example.

	“Drug development sponsors are being encouraged to partner with regulators, take more innovative risks, and amplify their concerns and ideas in terms of clinical trial quality and compliance,” said Peña. “With more time to process learnings from new technological implementations, the industry will begin to see additional standards for proactive clinical trial planning, execution, and quality-by-design.” In the long-term, companies will save time and expense from identifying anticipated risks early on through the refinement of current processes, she added.

	RBx is about investing in the future by improving quality and effectiveness. Roundtable attendees agreed that while holistic ICH E6 compliance has led to a modest increase in short-term operating costs, they expected to see substantial savings over time.

	Investing in the risk-based approach to the design and conduct of clinical trials is about the intelligent use of data to make informed decisions. It’s not only sponsors and CROs that are adopting risk-based approaches, but regulators are as well.

Roundtable gathers industry experts to discuss the guidance update’s early implementation and the shift toward risk-based study execution approaches.

How ICH E6 (R2) Offers Wins with Risk-Based Study Execution

	Participant safety is the clinical trial sector’s top priority - and striving to achieve this laudable aim also makes for more agile, flexible and efficient studies. That’s what we learned from a second executive roundtable discussion, hosted by the Tufts Center for the Study of Drug Development (CSDD), and supported via an educational grant from CluePoints and Pricewaterhouse Coopers, on the progress the industry is making towards implementing the requirements of the ICH E6 (R2) addendum. 

	Two years after being ratified, sponsors, CROs and sites have found the industry-wide shift towards Risk-Based Study Execution (RBx) is not only reducing risk, but improving oversight and boosting proactive, predictive decision making.

	When it was introduced in 2017, ICH E6 (R2) represented the biggest change to international clinical research in two decades. Developed as a response to the rising complexity of studies and the industry’s increasing reliance in electronic data management and reporting systems, it sought to define good risk management in the modern trial environment. It states that clinical programs should implement risk assessment at both the trial and system level, and that metrics on clinical monitoring and data management to be captured in preparation for Clinical Study Reports.

	Following the addendum’s publication, Tufts CSDD held the first roundtable on the updated guidance and found companies in the early stages of a big change. Director of Sponsored Research and Research Associate Professor at Tufts CSDDKenneth Getz, organized and facilitated the event with colleague, Yaritza Peña, a research analyst at the center. 

	“Two years ago, companies were in the early stages of interpreting the guidance to translate recommendations into tangible operating practices,” said Getz. “Roundtable participants indicated their initial focus was largely on risk-based monitoring (RBM). They were beginning to implement risk assessment procedures to identify which operating practices were most impacted. Although apprehensive about how the addendum would affect their current Standard Operating Procedures (SOPs), the attendees had all agreed that the revised guidance was a step towards more agile, flexible and efficient clinical trials,” he added.

	These latest discussions, held in Boston in April, found the organizations had made significant progress on a granular level, and were now taking a more holistic view. A total of 41 participants from organizations including Alkermes, GSK, MCCC, Pfizer, Roche-Genentech, Sage Therapeutics, Takeda and the FDA took part.

	After a panel discussion about the state of ICH E6 (R2) compliance, the companies offered up their own case examples before addressing the barriers and anticipated direction of travel. They found that rather than focusing simply on risk-based monitoring, the industry has been working towards improving study efficiency overall, by taking a much broader view of Risk-Based Approaches to Study Execution, or RBx as it is now being known.

	“Company mindset has progressed from 2017,” said Peña. “Since then, many organizations have incorporated a risk-based framework across end-to-end development processes. Companies are refining the quality management plans developed during the planning and execution stage, and using technology to drive pattern identification, machine learning and study-specific analysis.”

	The discussions found the new regulations had compelled companies to move away from a CRA-centric, on-site visit model of monitoring to a data-driven, central statistical approach that improves data quality and contributes to overall trial success. Roundtable participants said that utilizing technological solutions had enabled a risk-based approach, informed by objective data integration, that supported the critical thinking vital to being able to make the right patient safety decision at the right time. 

	Amanda Hayden, Director of Global Clinical Services at Alkermes, said the industry had experienced “significant maturation” with respect to its response to ICH E6 (R2). “While many companies may have approached the ICH update by addressing each subpart separately, the reality is that many of the processes are interconnected. Advancing clinical processes in a holistic fashion and thinking of risk in all facets of study planning, execution and analysis creates synergies and efficiencies, and allows for better use of time, resources, and study data.” 

	The companies chalking up success in this area are those that have recognized the opportunity and have since worked to reorganize SOPs and pathways to allow for a portfolio, rather than program-wide view. 

	They are making significant investment in analytical capabilities that not only apply to risk-based monitoring and oversight, but also to operational outcomes such as enrollment and protocol feasibility. Advanced data visualization, for example, can automatically detect trends and anomalies, and automated query management systems assist with the reconciliation of serious adverse events. 

	Study optimization is a natural consequence of utilizing these metrics, which allow companies even more sophisticated ways to distinguish between reliable and potentially unreliable data, and to avoid unnecessary protocol complexity. These opportunities are only set to increase as analytical techniques, including machine learning, natural language processing and other types of artificial intelligence are put to use in the clinical trial space.

	Achieving this holistic approach isn’t without its challenges and integrating ICH E6 (R2) concepts in study planning and implementation is proving difficult for some sponsors. “Part of the challenge depends on the creation of an efficient interface between a proactive quality planning process and a risk-based monitoring process,” said Getz. “Another daunting task is shifting company culture to adapt to the necessary changes to study processes when anticipating risk and performance issues.”

	“Since risk management is not currently a core operational competency, employees require training and monitoring to understand concepts such as data quality vs. data integrity, site monitoring vs. trial monitoring and data reliability vs. trial results reliability,” explained Getz.

	The companies currently embracing the opportunities of RBx have fundamentally changed the way data are verified, reviewed, analyzed and managed within their organizations. This has taken commitment from senior leadership and a wholesale change both in company structures and culture. Strategies employed have included robust change management training and the digital upskilling of staff. Clinical study teams, tasked with examining ICH E6 (R2) requirements to ensure the right data quality oversight tools are being used, have also been set up.

	Some industry players have developed teams of subject matter experts (SMEs) with the responsibility to ensure the guidance is implemented. These SMEs are able to take an overarching view of risk identification, reporting and evaluation, cross-functional sharing of risk and the monitoring of risk control measures across studies and protocols.

	“This horizontal view, that rises above separate protocols and sites to take in the bigger picture, is the key to realizing the potential of RBx,” said Hayden. “The main drivers in successfully implementing a risk-based approach to study execution is to consider the interconnected nature of risk identification and analysis throughout the entire lifecycle of the clinical program,” she added.

	While many of the companies at the roundtable said the project had increased operating costs, they also said these were offset by the benefits in terms on risk mitigation and proactive decision making. As clinical trials become ever more complex and fragmented, RBx systems can be used to continue to consolidate and streamline studies while allowing for strategic oversight. In fact, many of the roundtable companies said they believed they were better placed to drive effectiveness and optimize performance in the next three to five years.

	Those with the framework of RBx in situ appeared best placed to leverage the rich data that will be generated by ever advancing analytics. While AI utilization is still in its infant stages, for example, the roundtable participants expect it will soon play a role in efficiently identifying areas of risk and be able to guide stakeholders to the best possible solutions. They are also in the best position to respond to expected regulatory changes-the FDA is currently looking at revisions for E8 as well as a proposal regarding the next iteration of E6, for example.

	“Drug development sponsors are being encouraged to partner with regulators, take more innovative risks and amplify their concerns and ideas in terms of clinical trial quality and compliance,” said Peña. “With more time to process learnings from new technological implementations, the industry will begin to see additional standards for proactive clinical trial planning, execution and quality-by-design.” In the long-term, companies will save time and expense from identifying anticipated risks early on through the refinement of current processes, she added.

	Investing in the risk-based approach to design and conduct of trials is about the intelligent use of data to make informed decisions. It’s not only sponsors and CROs that are adopting risk-based approaches, regulators themselves are investing and implementing the same methodologies. For example, FDA is using these techniques to interrogate submission data with a view to selecting sites for inspection based on the results. The data-driven approach detects ‘anomalous’ data in sites that may have previously gone undetected, allowing regulators to focus their attention those sites. 

The industry-wide shift towards RBx is not only reducing risk, but improving oversight and boosting proactive, predictive decision making, writes Cluepoints' CCO, Patrick Hughes.

How ICH E6 (R2) Provides a Win/Win/Win through Risk-Based Study Execution

	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.”

 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.

	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.

 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

 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.

https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Addendum_Step2.pdf

		Society for Clinical Research Sites. 2017. SCRS InFocus. 

http://myscrs.org/assets/infocus_archive/InFocus_Archive_November_2017-updated.pdf

		An Updated Look at Risk Assessment and Risk-based Management Practices. MCC Industry Practices Insight Reports. Metrics Champion Consortium: 

		INTEGRATED ADDENDUM TO ICH E6(R1): GUIDELINE FOR GOOD CLINICAL PRACTICE E6(R2) - 

https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Step_4_2016_1109.pdf

		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.

 is Chief Commercial Officer for CluePoints.

, Information on their ICH E6 (R2) compliance and RBM adoption is here 

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

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

	The release of the ICH E6 R2 guidance, which outlines a new approach to clinical trials operations, will have a major impact on the industry. In response, and to better understand the perception of the new guidance by pharmaceutical companies, Tufts, CluePoints, and PWC organized a roundtable, which included senior executives from top tier pharmaceutical organizations that have responsibility for facilitating the changes required by the new guidance. The roundtable sought to highlight the main aspects of the guidelines, how organizations are responding to it, and the challenges they now face in an effort to achieve a common level of understanding across the organizations.

	Generally, the roundtable highlighted a positive attitude towards the guidelines, with executives seeing the introduction as an opportunity to make significant changes to the industry. Clinical trials are becoming more complex and costly, and still rely on the same processes that have been in place for decades. As this process becomes unsustainable, change must be made in the way clinical trials operate to ensure the industry continues to move forward. The introduction of the new guidance enables key decision-makers to accelerate adoption of technology to ultimately improve resource efficiency, data quality, and study timelines.

	All of the organizations represented at the roundtable have already discussed and made plans to accommodate the guidelines, and most have made progress into the types of activities that are recommended. Prior to the guidance being introduced, most organizations had already recognized that a risk-based monitoring approach is the way forward, with a general consensus that this approach must be adopted in every study to become the norm. The ICH E6 R2 states that organizations should develop a systematic, prioritized, risk-based approach to monitoring clinical trials, which has given organizations the momentum they have needed to start implementing this type of approach.

	Although the new guidelines have only recently come into effect in Europe with other regions to follow soon, and it is still early days for the industry, representatives at the roundtable highlighted what will likely be the main challenges in implementing this change. The reorganization of processes which have been imbedded for years will take time and effort, and staff members will have to be trained to properly incorporate new technology into the organization. Additionally, each organization currently has a different approach, and will have to adapt the changes needed to the processes they already have in place. For example, the most variable decision highlighted at the roundtable is how organizations are going to monitor clinical trials, and whether to take a centralized or decentralized approach, or a mixture of both. 

	The roundtable has shown that the pharma industry is ready to embrace more efficient approaches to trial design. Rather than a hurdle, many organizations are seeing it as an opportunity for more efficient clinical research; however, there will be more challenges ahead as organizations start to implement the necessary changes.

	For more information on how companies are responding to the addendum, and the challenges the industry now faces, please download a full report from the roundtable discussion here: 