ICH GCP E6 (R2) – It's All About Effective Oversight … And Pizza!
By Beth Harper
To some extent, the Integrated Addendum to ICH E6(R1): Guideline For Good Clinical Practice E6(R2)1, released Nov. 9, 2016 (and affectionately referred to as ICH E6 (R2)) has come and gone without much fanfare. Perhaps that’s because prior guidance documents surrounding risk-based quality management practices stole its thunder, and sponsors, CROs, and investigators were already well on their way to finding ways 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,” as advocated by ICH E6 (R2). Certainly, there is no shortage of articles, webinars, and vendor presentations providing recommendations on how to implement quality risk management (QRM) initiatives, but it is the oversight aspects of ICH E6 (R2) that have me most interested from a practical perspective.
First, it is interesting to note that the word “oversight” appears three times in the addendum, whereas the original version doesn’t mention oversight at all. While the number of mentions may not be significant, it is the spirit of the oversight processes that gets a lot of attention in the addendum. As someone who spends most of her time troubleshooting trials with enrollment and other site performance problems, I have observed many project teams struggle with CRO and investigative site oversight. With regard to CRO oversight in particular, sponsor teams have always appreciated the need to “ensure oversight of any trial-related duties and functions carried out on its behalf,” but the new addendum formalizes this a bit more by placing greater emphasis on the sponsor’s oversight responsibilities. How to do that in an applied and meaningful fashion is where I see teams struggle the most.
To start, it’s worth visiting a few definitions and concepts: oversight, accountability, and trust. Oversight can be defined as the process of overseeing something. To oversee something is to watch over and direct (an undertaking, a group of workers, etc.) in order to ensure a satisfactory outcome or performance.
Some guiding principles for all oversight processes should include2:
- Transparent communication,
- A clearly established expectation for quality,
- A precise definition of accountability and responsibility while avoiding silo mentality, and
- A comprehensive documentation of the oversight’s evidence.
Accountability is wrapped up entirely in expectations — the results that are expected to be produced. Finally, trust means that we have confidence in the intentions and motives of the other party. For sponsors, this means they have confidence that the CRO will be accountable for delivering results. This is the piece of the equation that really breaks down in my experience.
The more risk involved in a trial, the more oversight is needed, hence the focus on risk-based monitoring and trial management within ICH E6 (R2). But practically speaking, sponsors often feel the greatest need to enhance oversight of their CRO (or other service provider) partners when they don’t trust them to deliver, have lost confidence in them, and/or see evidence that their partners are not being accountable for delivering on expectations. If trust and accountability levels are high, less oversight is required.
For many in the industry, when trust starts to erode, more oversight is needed. The application of this oversight is often translated into more micromanagement of the CRO, which is counterproductive and costly, not only from a financial perspective but also from a relationship perspective. Micromanagement is oversight by hovering over every process and activity. Theoretically, it’s possible to minimize the need for micromanagement by ensuring all parties are 100 percent clear on the outcomes they are charged with achieving, there are good systems and metrics in place for monitoring progress, and adjustments can be made in a timely and collaborative manner. Stepping in at critical times is part of the oversight process, but to be effective, there has to be some level of trust between the sponsors and CROs (and by extension, these parties and the investigative sites).
A recent industry survey paints a fairly depressing picture of the level of trust and confidence between sponsors and CROs. According to the survey, only 34 percent of clinical operations leaders indicated that they had successfully achieved their planned CRO goals, and when asked if they had confidence in being able to achieve their CRO goals, only 22 percent of respondents responded positively.3 Trust and verify relationships are a two-way street, of course. To build trust, both partners must invest in and commit to the relationship. For CROs, this means:
- Meeting timelines
- Producing quality data
- Resolving issues through solution-focused action plans
For sponsors, this means:
- Engaging in a sincere partnership
- Providing critical information and responses to the CRO in a timely and decisive manner
- Collaborating in sharing best practices in issue resolution.4
As sponsors continue to wrestle with how best to implement CRO oversight, they often turn to “typical” quality management activities such as auditing, creating myriad quality and other SOPs, performing due diligence and training activities, creating responsibilities and assignment matrices (RACIs), and establishing communication and oversight plans. This leads to a large number of SOPs, guidance documents, forms, and templates, totaling in some cases more than 20 relevant documents to manage the oversight process.2 While the temptation is great to just document our way into better oversight, it is important to avoid overregulation, creating too many or unnecessary interfaces that can endanger the original goal of enhancing quality. Furthermore, all the documentation in the world can’t mandate that the CRO behaves in a more accountable fashion, nor can these efforts force a culture of trust. Trust has to be built and earned. Excellent resources abound for how to do this, including those noted incitation No. 5. Personally, I prefer the pizza methodology.
Need a refresher on all of the changes that came with ICH E6 R2 Addendum?
Amazon CEO Jeff Bezos is known for sharing his leadership insights, such as how he decides which risks are worth taking and how he minimizes lost productivity due to unnecessary meetings. For the latter, he uses the “two pizza rule”: Never have a meeting where two pizzas couldn't feed the entire group.6 In this context, productivity is about communication and a function of group size to make decisions, which is not really the focus of this article (but worth noting for how sponsor and CRO leadership can come to consensus about some of the risk-related, accountability, and oversight processes noted above). It’s the pizza itself that is at the heart of establishing the trust necessary to ensure a successful sponsor-CRO relationship such that the sponsor can trust the CRO to deliver and avoid the need for micromanagement and/or unnecessary extraneous oversight documents.
In the world of social psychology, psychologists are increasingly discovering the importance of trust in friendships and professional relationships. It has long been assumed that trust must be built gradually, which is challenging to do in the high-stakes and rapid-paced world of clinical trial execution. In a recent study conducted by University of Chicago researchers, however, they found that trust can develop very quickly – sometimes over the course of a single meal. And the key ingredient to establishing trust was for all parties or members of a team to eat the same food.7
While the research is intriguing in and of itself, there are some practical applications to creating a culture of trust between sponsors and CROs. Ask yourself, when was the last time you actually met, let alone broke bread with your CRO partner? Think about meeting key members of your CRO team for lunch before you hit the “escalate” button on your oversight plan. Challenge yourself to critically evaluate whether you can swap out some of the 20-odd oversight documents for more trust-enhancing meals with your CRO partners. Finally, consider building into your oversight plan and study budget plenty of (two-pizza-sized!) face-to-face meetings before, during, and after the clinical trial. Just don’t forget to ask whether they prefer thin or thick crust!
References:
- http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Step_4.pdf
- Hennig, M. et al. 2017. Current practice and perspectives in CRO oversight based on a survey performed among members of the German Association of Research-Based Pharmaceutical Companies (vfa) Ger Med Sci. 2017; 15: Doc02. Published online 2017 Jan 26.
- Peacock, J. 2016. Achieving CRO Oversight. Applied Clinical Trials Online. Retrieved from: http://www.appliedclinicaltrialsonline.com/achieving-cro-oversight
- Arena International: Vendor-Sponsor Successful Communication. Nov. 2012. Retrieved from: http://www.arena-international.com/journals/2012/11/22/v/v/m/1-pout-1012_dutil_presentation.pdf
- Asherman, I. and B. Sagotsky. Trust-based Influence and the Sponsor/CRO Relationship. 2009. The Monitor. Retrieved from: http://www.asherman.com/downloads/article-tbi-scro.pdf
- Cain, A. 2017. The 'two pizza rule' is Amazon CEO Jeff Bezos' secret to productive meetings . Business Insider blog post. Retrieved from: http://www.businessinsider.com/amazon-ceo-jeff-bezos-two-pizza-rule-productive-meetings-2017-6
- Lebowitz, S. 2016. A psychological trick to get people to trust you is best used over lunch. Business Insider blog post. Retrieved from: http://www.businessinsider.com/get-people-to-trust-you-by-eating-the-same-food-2016-7
About The Author:
Beth Harper is the president of Clinical Performance Partners, Inc., a clinical research consulting firm specializing in enrollment and site performance management. She has passionately pursued solutions for optimizing protocols, enhancing patient recruitment and retention, and improving sponsor and site relationships for over 30 years. Beth is an adjunct assistant professor at the George Washington University and has published and presented extensively in the areas of protocol optimization, study feasibility, site selection, patient recruitment, and sponsor-site relationship management. Beth is currently serving on the CISCRP Advisory Board as well as the Clinical Leader Editorial Advisory Board, among other industry volunteer activities.
Beth received her BS in occupational therapy from the University of Wisconsin and an MBA from the University of Texas.
She can be reached at 817-946-4782 or bharper@clinicalperformancepartners.com.