ICH E6 R2: Talking Big Pharma’s Response To The Addendum

This article was originally produced for Clinical Informatics News

The introduction and implementation of ICH E6 R2 has raised many questions surrounding operational risk-based approaches to clinical trial oversight. With the industry now in the process of getting to grips with more modernized practices for study conduct mandated by the guidance, this article addresses how sponsors are working to understand and interpret the obligations, as well as overcome the resulting challenges.

To better understand the impact of ICH E6 R2 (see, New GCP R2 Guideline Emphasizes Risk Management Through People, Process, And Technology) and the perception of the new guidance by pharmaceutical companies, Tufts, CluePoints, and PricewaterhouseCoopers (PwC) organized an industry roundtable, which brought together 34 senior executives from major pharmaceutical companies, including Allergan, Johnson & Johnson, Pfizer, GSK, Novartis, Biogen, Takeda, and Amgen. The roundtable sought to highlight the main aspects of the guidelines, how organizations are responding, and the challenges they now face in achieving a common level of understanding across their businesses.

Talking Points

The majority of the companies shared that they are still in a consultation phase where they are interpreting the guidance and translating the recommendations into tangible operating practices. Instead of a negative “more guidance to comply with” attitude, the overwhelming consensus was that ICH E6 R2 presents a real opportunity to drive long-overdue change while making trials more agile, flexible, and efficient. Most attendees confirmed that their organizations had made considerable progress and have the amendment as a priority item to address. Several attendees said they are in the process of identifying critical variables for their trials (e.g., relevant critical-to-quality factors), while others are working with their technology departments to incorporate statistical algorithms and account for the sensitivity of smaller trials.

To address the recommendations on documentation, some companies are identifying specific monitoring approaches in their quality management, creating data surveillance plans managed by statisticians, and including signatures on reports to confirm adherence to monitoring plans. Companies are also starting to perform risk assessments and gap analyses of organizational procedures to determine the areas that have the most impact on the credibility of data and will be most impacted by ICH E6 R2. The roundtable demonstrated that many companies are shifting monitoring from a CRA-centric, site visit model to a central monitoring methodology incorporating more data-driven, statistical approaches. They are committing to improving data quality with a long-term goal of reducing cost.

The industry is, as we all know, uber-conservative and, as a result, there hasn’t been much in the way of change or advancement in how clinical trials are conducted for decades. Antiquated processes are the norm. The way clinical trial pipelines are currently being managed is also unsustainable due to increases in protocol complexity and growing costs from requirements such as 100% source data verification (SDV). For many larger trials, as much as 30% of all costs can be attributed to monitoring, and 50% of those costs are due to labor-intensive SDV. Having the opportunity to approach trials from a Risk-Based Monitoring (RBM) perspective presents a huge opportunity. Companies are recognizing that the introduction of the guidance has enabled them to accelerate adoption of RBM, so they can begin reaping the rewards in terms of cost and resource efficiency, and improved data quality and timelines. This is giving them more impetus to get change in motion and fully embrace it.

Since the guidelines came into effect, there is a real sense from pharmaceutical companies that ICH E6 R2 has validated the RBM approach, accelerating a faster adoption cycle than would have otherwise played out. Most companies recognize that RBM is the way forward, and have already taken steps to prove the concept, and there is drive towards adoption in every study. While it may have been acceptable and inevitable to see adoption of electronic data capture (EDC), electronic patient reported outcomes (ePRO), and electronic clinical outcomes assessments (eCOA) take 10-15 years to become the industry standard, the benefits of RBM mean that the timeframes need to be in the region of three to five years. The regulators are making sure that this happens.

Industry Challenges

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 embedded 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 was how organizations are going to monitor clinical trials, and whether to take a centralized or decentralized approach, or a mixture of both.

Another significant challenge highlighted was the process of transforming an organization’s culture to change the way risks are identified and managed in clinical research. Issues in selecting appropriate sites when developing a RBM approach and establishing algorithms that are specific but can be applied to a broad set of therapeutic areas were also discussed. Finally, many attendees also revealed that they felt more clarity was needed on how the regulators intend to assess quality risk management plans.

Final Thought

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 no doubt be more challenges ahead as organizations start to implement the necessary changes

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