ICH E6 R2: Waiting and Watching no Longer an Option When it Comes to Risk-Based Monitoring

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As is typical of our industry, despite ringing endorsements of Risk-Based Monitoring (RBM) from both the FDA and EMA back in 2013, researchers have been conservative with respect to adopting this proven approach as standard within their clinical trials.

However, the introduction of ICH E6 R2 this year means that waiting and watching is no longer acceptable. The updated guidelines finally makes it official; a risk-based approach to clinical trial quality management – commonly referred to as Risk-Based Monitoring or RBM – is now a codified GCP expectation for the industry.

The updated ICH E6 R2 guidelines have been introduced to encourage implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, recording and reporting while continuing to ensure human subject protection and reliability of trial results. The ICH E6 R2 states that, “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.”1

So for those who have been resisting the shift, often simply through fear of change, the time is now to sit up and take action when it comes to implementing an RBM approach within your trials. RBM offers the chance to significantly improve quality, shorten study timelines and do this all at significantly lower cost, so embracing it should be viewed as a huge opportunity and positive step forward in carrying out more efficient clinical research.

There is no doubt that many sponsor and CRO organizations that may have previously delayed implementation of RBM methodology will be now be pouring over the updated guideline to determine what is needed for compliance. The guidance recommends that the approach taken must be controlled and systematic for the lifecycle of the study, and sets clear expectations for appropriate monitoring methodologies and documentation, including critical process and data identification, risk identification, risk evaluation, risk control, risk communication, risk review and risk reporting.

While it may sound complex, it is important for organizations to know that RBM strategies can be relatively straightforward to implement, providing they work collaboratively with the correct study partners to identify and implement the right tools that will help them manage this change in the most effective way and reap the advantages as soon as possible.

Once implemented, it’s crucial to make RBM stick and study teams can do this by ensuring clear communication with all involved in the change, creating an environment of openness where discussion about the new approach is encouraged, avoiding information overload, and continuously checking understanding to ensure correct processes are being followed.

For further insight, check out this month’s ACRP Clinical Researcher, in which I discuss ICH E6 R2 in more detail and explain why organizations should shift their mind-set away from simply ensuring compliance, and towards embracing the tremendous business opportunity offered through an effective roll-out of RBM. (Link to final piece to be included)


  1. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002874.pdf

This article was produced for the Association of Clinical Research Professionals 

CluePoints Opens U.S. Office

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2 May 2017

Wayne, PA – CluePoints, a leading provider of Risk-Based Monitoring (RBM) and Data Quality Oversight solutions for clinical trials, today announced that it will be expanding its operations in the U.S. with the opening of a new office in Wayne, PA. The expansion marks a key milestone in CluePoints’ ambitious growth strategy that will see the company build its infrastructure to support its rapidly growing U.S. client base.

CluePoints, which already provides its solutions to seven of the top ten global biopharmaceutical companies and notable CROs and medical device companies, has seen demand for its services increase, fueled by growing industry and regulatory recognition of the benefits of a centralized statistical monitoring (CSM) approach. As a result, CluePoints has already grown its U.S. commercial team with the appointment of two new business development executives, and over the next 12 months the company will increase its staff by 50%.

CluePoints’ U.S. operations are being led by Steve Young, chief operations officer, who will be supported by project managers and data analysts at the new office. Their focus will be on developing and supporting both existing and new customers in the region, from small and mid-size organizations to large pharmaceutical companies and CROs.

“A strong presence in the U.S. is a critical next step in our strategy, following momentous growth in demand for our solutions. Not only are our customers experiencing significant tangible cost benefits but industry regulations, especially the imminent revised ICH E6 (R2) GCP guidance, now insist that sponsors have a central statistical approach to driving data quality, integrity and oversight,” comments Steve Young. “We chose Wayne, PA for our operations because it is located within a key region for biotech, CRO, pharma and technology companies, and provides access to a rich talent pool to support our continuing growth.”

For further information on CluePoints’ solutions, please visit www.cluepoints.com

About CluePoints

CluePoints® is a Risk-Based Monitoring and Central Statistical Monitoring solution that has been designed and perfected over the last 15 years. It employs unique statistical algorithms to determine the quality, accuracy, and integrity of clinical trial data both during and after study conduct. Aligned with guidance from the ICH, FDA and EMA, CluePoints® is deployed to support traditional on-site monitoring, medical review and to drive a Risk-Based Monitoring strategy. The value of using CluePoints® lies in its powerful and timely ability to identify anomalous data and site errors allowing improvement in clinical data quality, optimization of on-site monitoring and a significant reduction in overall regulatory submission risk.

Media contact

Patrick Hughes – Chief Commercial Officer, CluePoints
+44 (0) 7703 532 749

CluePoints’ Founder to Present on Risk-Based Monitoring at FDA/AdvaMed Conference

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The 10th Annual FDA/ADVAMED Medical Devices and Diagnostics Statistical Issues Conference, taking place on April 26, 2017 to April 27, 2017, brings together leading authorities from FDA, industry, and academia to address statistical topics through two tracks – therapeutic device and diagnostics. Hear directly from FDA and industry experts to better understand the latest statistical trends and issues facing medtech organizations today.

CluePoints’ Founder, Marc Buyse, will talk at a session on using Risk-Based Monitoring as a way to both improve data quality and streamline clinical trial costs. Marc will describe an implementation of Central Statistical Monitoring using software that automatically performs a large number of statistical tests on all available data in multicentre clinical trials, resulting in a high-dimensional matrix of P-values which are summarized in an overall score for each centre, the score is analogous to an average P-value, with the low scores indicating the centres that are statistically most different from all others.

Washington Marriott at Metro Center, 775 12th St NW, Washington, DC 20005


 If you haven’t registered already, we recommend registering soon to avoid disappointment.

See you there!

ICH E6 Rev 2 – Ask the Experts

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Last week, we hosted our second webinar of 2017, Implementing Risk-Based Monitoring – What Does the ICH E6 Rev 2 Mean for My Company? There were many great questions from the attendees. In fact, we had so many questions that we couldn’t get through them all! So as promised, we’ve documented the most common questions, along with our answers. Enjoy!

QRisk-Based Monitoring sounds like the FDA encouraging Sponsors to begin looking at Data from Sites earlier on in the Study timelines. So why are the Sites beginning to feel their “hair is now on fire” for faxing and copying HIPPA sensitive data over email and fax. This message/ perception needs to be looked at.  And know that R2 is an FDA to SPONSOR revision and should affect sites on a day to day basis

A:  Indeed Risk-Based Monitoring methodology does encourage pro-active monitoring of relevant data and information from across all participating sites in a clinical trial – with emphasis being placed on centralized monitoring using intelligent/statistical methods that help to identify sites that are outside of an expected range across various quality (or performance) measures.  This allows teams to direct their attention more effectively to clinics that may need some support to overcome particular challenges (training needs, etc.).  However, the practice of asking sites to fax or scan various patient source documents for remote review is not called for by RBM guidance/methodology.  This practice is being employed by some sponsors (for good or ill), and unfortunately, sites are being told that this is a part of “RBM”.  In our view – and based on the FDA and ICH guidance already provided – this is NOT part of RBM.

Q:  How does ICH E6 R2 impact Computer System Validation, if any?

A:  There are indeed several paragraphs added to the new R2 update that address aspects of Systems Validation.  We suggest you review those additions directly in the current final version (publicly available).

QRemind us when patient profiles will be rolled out in CluePoints

A:  Patient Profiles are available with our April release – in two weeks!

Q: ICH E6 R2 indicates the need for monitoring reports for central monitoring.  We recognize central monitoring may be conducted by various roles (dedicated resources, plus physicians, scientists, quality, data managers, etc.) and is done on an ongoing manner.  Any insights on how to best document central monitoring activities in a ‘report’ without overburdening the organization?

A: What documentation is created is dependent on where and how the monitoring activities are occurring. The most important element is defining, up front, the process, audit trail (if there is one) and criteria for assessment/outcome determination and action/escalation.  There are 2 primary ways to capture central monitoring activities in a report format: 1. A simple event-driven report typically created by the user completing the assessment listing/describing data reviewed/outcomes/actions. Or 2.  An end of study or scheduled summary report of activities that lists the activities/outcomes undertaken in a specific timeframe or throughout the study (e.g. in an RBM platform, like CluePoints). The objective of capturing the evidence of your central monitoring activities is to demonstrate that you are adhering to your monitoring plan and addressing the risk appropriately.

Q: Will you please address with ICH E6 R2 takes effect in US and EU?  In other words, when are sponsors expected to make sure their studies comply with the new guideline. 

A: ICH E6 R2 is expected to be effective in Europe, per the EMA, as of 14 June, 2017, and the FDA has not set an effective date as of today.

QHow do one can detect fraud in RBM studies?

A:  There are a number of statistical tests that can be very helpful in detecting fraud in clinical research, and we recommend using a combination of these to be most effective.  A few to consider:

– Variability testing:  looking for unusual lack of variability in patient measurements for a single patient (e.g., across visits) or across patients within one site.

– Mean values:  identifying patients whose mean measurements are consistently in a different range than other patients within the study.

– Timing of Events:  As in the ePRO fraud case that we discussed, looking at an unusual distribution of patient event dates or times can be helpful as well.

Q:  Do you have any recommendation of document that we can study for identifying KRI?

A:  We suggest visiting the TransCelerate RBM website, which posts publicly available RBM guidance materials including a suggested library of KRIs to consider.  The Metrics Champion Consortium (MCC) has also developed a list of KRI definitions – with more detailed guidance on KRI algorithms and thresholds.  Access to the MCC materials requires membership first.  CluePoints also has deep expertise in KRI methods and best practices and offers consulting in this area (and RBM methodology in general) if you are interested.

QDo you know what type of data errors were typically caught by SDV? e.g. unreported AEs? 

A:  Indeed the analysis we performed revealed that SDV had a relatively bigger impact identification of unreported AE’s (7% to 12% of total AEs) than on finding data entry errors (1% of data).  Our conclusion was not that you should do 100% SDV of AE’s, but that relatively more SDV focus should be put on AE reporting than on other data.

Q:  Do you have any examples of effective rationale documentation for the chosen monitoring strategy

A:  An appropriate rationale will associate the identified and assessed risks related to the study’s critical data to the specific mechanism of review and evaluation specified in the plan. In other words, the monitoring strategy has to show that you have control and oversight in place for data points that impact safety and study outcome.

Risk-Based Monitoring Software

Webinar Recording: What Does ICH E6 R2 Mean for Me and My Company?

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This week, CluePoints hosted a webinar with Paragon Solutions, which was geared towards preparing attendees on how to take advantage of the ICH E6 revisions to ensure appropriate consideration of risk in study design and management. Attendees learned about the key ICH E6 updates related to Risk-Based Monitoring and their purpose, how Central Statistical Monitoring and Key Risk Indicators will work for them, and how to use the E6 R2 to support their organization’s transition to Risk-Based Monitoring.

If you missed the webinar, you can access the on-demand recording here. Please feel free to share the URL with your colleagues.

We hope to see you at future CluePoints webinars!

Patient Profiles Image

CluePoints Launches Patient Profiles as Latest Addition to its Risk-Based Monitoring and Data Quality Oversight Solution

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13 March 2017

Cambridge, MA – CluePoints, a leading provider of Risk-Based Monitoring (RBM) and Data Quality Oversight solutions for clinical trials, has introduced Patient Profiles to its rapidly expanding platform. The powerful combination of Patient Profile reports, guided by CluePoints’ advanced central statistical monitoring, offers a new way for clinical teams to prioritize the investigation of atypical patients in clinical trials.

Patient Profiles provides detailed insight into patient experiences and offers a more targeted approach by identifying anomalies in data and ranking patients by their relative degree of atypicality.  The highly configurable Patient Profiles solution presents a rich set of customizable visualization options, including the ability to visually assess a chronological view of a patient’s visit, investigational product exposure, adverse events and concomitant medications – along with any additional relevant patient information. The solution will help to enhance overall quality management, guiding study teams to quickly and effectively characterize risk signals and enable centralized medical and safety reviews within the CluePoints platform.

“The addition of Patient Profiles to CluePoints’ portfolio aligns with our vision of expanding data exploration capabilities at both the patient and site level,” commented Steve Young, chief operations officer at CluePoints. “Reinforced by the voice of our customers, the solution will revolutionize the patient profiles review process by prioritizing and illuminating ‘at risk’ patients.

“Our agile product methodology is enabling us to rapidly evolve our solutions and exceed the expectations of our customers, delivering tangible value to them. This latest addition will significantly improve the efficiency of patient data review processes because customers can target their efforts on the patients and data that matter most.”

For further information on CluePoints’ solutions, please visit www.cluepoints.com

About CluePoints

CluePoints® is a Risk-Based Monitoring and Central Statistical Monitoring solution that has been designed and perfected over the last 10 years. It employs unique statistical algorithms to determine the quality, accuracy, and integrity of clinical trial data both during and after study conduct. Aligned with guidance from the FDA and EMA, CluePoints® is deployed to support traditional on-site monitoring and to drive a Risk-Based Monitoring strategy. The value of using CluePoints® lies in its powerful and timely ability to identify anomalous data and site errors allowing improvement in clinical data quality, optimization of on-site monitoring and a significant reduction in overall regulatory submission risk.

Media contact

Patrick Hughes – Chief Commercial Officer, CluePoints
+44 (0) 7703 532 749

CluePoints COO, Steve Young, to Present on Statistical Probability Analysis at MCC’s Central Monitoring Workgroup

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The Central Monitoring Workgroup will feature speakers from several solution providers who will each present and discuss the types of analytic methods that are relevant for centralized monitoring and data quality oversight.  The first speaker will be Steve Young, COO at CluePoints (and the Metrics Champion Consortium’s Central Monitoring Workgroup leader), who will talk about Statistical Probability Analysis including the specific types of operational issues that it can uncover.

The goal with this series is to help the MCC community to better understand the types of analytics available and how each of them can help to drive effective centralized monitoring.

Webinar Date & Time

Wednesday, 15 March 2017, at 10:00am -11:00am EST

Patient Profiles unveiled as latest addition to CluePoints’ Risk-Based Monitoring and Data Quality Oversight solution

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We’re thrilled to announce that version 1.11.0 of CluePoints’ Central Monitoring platform, the enabling SaaS platform for Risk-Based Monitoring,  will be available to users in April!  Version 1.11.0 adds an abundance of new features (as requested by customers) and extensions to existing functionality.

There’s lots to cover, so let’s get started.

Patient Profiles

We have added Patient Profiles to the platform. Users can design and customize the patient profiles template using an intuitive and visual interface.

Patient profiles offer a new way to investigate atypical patients by looking at summary information from different datasets. Different data representations are available: tables, graphs, and Gantt chart.

Machine Learning(Beta Version)

We have trained a machine learning model to help users to benefit from decisions made in the past. A model has been distilled from 10 million scores in order to predict scores that should be associated with signal. In this first version, a machine learning model is used to assist the user in deciding which scores should be linked to a signal. In terms of user interface, a filter allows the user to only display the scores that need to be linked to a signal. The user can confirm which scores are signals and which scores are false positives.

Improved Key Risk Indicators

Based on the feedback we have received from our users, we have made some improvements in the Key Risk Indicators:

  • No minimum volume of data required: Previously KRIs were only displayed when enough observations to fit a statistical model were available. In the new version it is possible to assess sites using KRI absolute value thresholds even if it is not yet possible to fit a statistical model.
  • Improved user experience and navigation: We have added additional filters, and better organized the information on screen to facilitate the assessment and review of the KRIs.

That’s all for now!

If you would like a demonstration of the new features, please email contact@cluepoints.com.

About CluePoints

CluePoints is the premier provider of Risk-Based Monitoring and Data Quality Oversight Software. Our products utilize statistical algorithms to determine the quality, accuracy, and integrity of clinical trial data both during and after study conduct. Aligned with guidance from the FDA, EMA, and the new ICH (E6) addendum, CluePoints is deployed to support traditional monitoring and data management and can be implemented as the ultimate engine to drive Risk-Based Monitoring. The value of CluePoints lies in its powerful and timely ability to identify anomalous data and site errors allowing optimization of central and on-site monitoring and a significant reduction in overall regulatory submission risk.

Like this post? Follow @CluePoints on Twitter for blog post alerts, industry news, and more!

6th Annual CROWN Congress: Sessions you Can’t Afford to Miss + 15% Discount Code

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It’s really no secret that the evolving regulatory landscape for clinical trials is a hot topic amongst the community. Just take a look at the agenda for the 6th Annual CROWN Congress, it’s jam-packed with sessions focused on the eagerly anticipated ICH E6 revisions, the new EU 536/2014 clinical trial regulations, risk management and centralized monitoring.  Of course, with the increased pressures coming from the regulatory bodies, sponsors are racing to implement recommendations to ensure that their clinical trials run in line with guidance.

With that in mind, we’ve put together a list of the #CROWNClinical ’17 sessions that you absolutely can’t afford to miss:

  • Risk-Based Monitoring and the Centralized Monitoring Model – Mapping out and Executing a Centralized Monitoring Approach to Optimize Operational Quality and Efficiency

    Speaker: Steve Young, Senior VP of US Operations, CluePoints
    Date & Time: Wednesday, March 8, 2017, at 3:30pm

  • Changing Regulations – Evaluating the Changing Global Regulatory Environment and the Impact on Clinical Risk Management

    Speaker: Doreen McGirl, North America Lead, Global Quality Business Operations, Otsuka
    Date & Time: Thursday, March 9, 2017, at 08:30am

  • Proactive Risk Management – Proactively Planning for Risk Realization and Managing Response

    Speaker: Stephen Potter, Director, Clinical Development Quality, Pfizer
    Date & Time: Thursday, March 9, 2017, at 09:15am

  • Clinical Operational Shifts – Examining how Evolving Regulations, Quality Expectations and Risk Assessments are Driving Changes in Clinical Operations

    Speaker: Federico A. Feldstein, J.D., Vice President, Global Head of Bio Research Quality and Compliance, The Janssen Pharmaceutical Companies of Johnson & Johnson
    Date & Time: Thursday, March 9, 2017, at 1:00pm

Not registered yet? – use discount code ‘C846CLUEPOINTS’ to save 15% on registration.

If you would like to schedule some time to discuss the upcoming regulatory revisions, Risk-Based Monitoring implementation, or anything else, please send an email to contact@cluepoints.com

See you there!

Six Ways to Get the Most out of Outsourcing in Clinical Trials West Coast ‘17

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There’s only a couple of weeks to go until Arena’s flagship event, Outsourcing in Clinical Trials West Coast returns to Burlingame. The must-attend event brings together over 700 clinical professionals from the Bay Area and beyond, to discuss clinical outsourcing strategies and overcome key challenges within clinical operations. From sessions to booth activities to after-hours events, there will be lots to do while you’re in San Francisco. Whether you’re a first-timer or a seasoned attendee, here are 6 things you can do to make sure you get the most out of this year’s conference:

Find out who's going

Following #OCTWestCoast on Twitter is an excellent way to find out who will be at this year’s event. Tweeting your plans to attend and getting involved in conversations ahead of time is a great way to make your presence known as well. You may also want to follow @CluePoints for live updates during the event.

Plan ahead

Arena International provides the full conference schedule in advance, so it’s easy for you to build your personal session schedule before you head out to Burlingame. Take advantage of the agenda to decide on sessions that you would like to attend.


Preparation is key. Think of the questions you would like to have answered and don’t hesitate to ask them during the Q&A’s for the sessions you attend. If you don’t feel like asking your questions in front of an audience, you can have a chat with the speaker afterward.


Attending outsourcing in Clinical Trials West Coast isn’t only about attending sessions, it’s also about networking. More than 700 people from the clinical operations community are expected to attend the event, which leaves lots of opportunity for learning from peers. We highly recommend attending after parties to get advice, exchange ideas, and make those all-important connections with members of the clinical operations ecosystem.

Strike while the iron is hot

Don’t wait to follow up until the conference is over. Use the momentum of the event and send follow-up emails and Linkedin requests while the conference is still fresh in people’s minds. Take notes on the business cards you collect so you don’t forget the most important points of discussion. Even better – use business card apps such as CamCard to store all of the information digitally.

Share what you learn

Make sure that you share your key takeaways and learnings. Set up informal meetings with your colleagues and managers to share your newly acquired insights. Use social media – whether it’s Twitter, Linkedin and/or Facebook to share what you learned at the show for a more immediate impact.

Join us at the event

If you’re going to be in Burlingame, be sure to stop by booth #31 to meet our Risk-Based Monitoring and Data Quality Oversight subject matter experts!