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Business & Regulation Standards & Regulation, Clinical Trials

The Sacred Texts

The end of 2021 – or, should I say, the beginning of 2022 – heralds a new dawn for sponsors, sites, and CROs. Why? Because the International Conference on Harmonisation (ICH) is in the final stages of publishing two long-awaited documents. Both scheduled for adoption in late 2022, they describe internationally agreed upon Clinical Research principles and practices designed to support regulatory acceptance.

The first document, E8(R1), includes fresh guidance on clinical trial design; the second, E6(R3), is a revised document, covering trial conduct. These two updates will be largely welcomed by the industry but planning for – and actually achieving adherence to them – will be a long journey for most organizations.

Becoming fully compliant with the new and upcoming ICH guidance documents is necessarily a journey – and one that organizations must traverse at their own pace.

Recent years have seen manifold changes in trial design and technology, rendering much of the documents’ content out-of-date long before publication. Since ICH inception in 1990, clinical study design and conduct have become significantly more complex, impacting the time and cost required to develop drugs. From 1990 to 1999, the cost of drug development totalled approximately US$1 billion per drug, but this figure has more than doubled in the years that have followed, reaching around $2.6 billion today.

A much broader range of study designs, data sources, and formats – plus increased involvement of central testing facilities or other service providers – now play a key role in drug development. The update intends to address a broader range of clinical trial designs and data sources, and to stress that clinical trials should embody the principles of “Quality by Design” (QbD). The ICH E8(R1) guidance now clearly focuses on “critical to quality factors” to protect study subjects, maximize the reliability and interpretability of the study results, and maximize confidence in the decisions based on those results.

A more integrated and proactive approach to QbD is becoming the new gold standard. When designing their studies, sponsors and CROs are identifying quality factors, anticipating the probability and impact of the risks, and then deciding whether they can be accepted or should be mitigated, rather than trying to tackle them as they arise. By focusing on QbD from the outset, trials can be designed to provide better and more reliable data at a much lower cost. Most importantly, however, these changes will mean safer trials for participants.

Becoming fully compliant with the new and upcoming ICH guidance documents is necessarily a journey – and one that organizations must traverse at their own pace. Striking the right balance between speed of adoption and managing organizational change can be tricky. Typically, there are five stages to go through: non-compliance (Level 1), to compliance with both E2 (Level 2) and E8(R1) (Level 3), compliance and active adoption of the principles (Level 4), and full optimization of the processes (Level 5).

As sponsors embark on this journey with the goal of achieving greater compliance maturity, they should first systematically evaluate their internal processes to ensure full adoption of E6(R2),  and secondly evaluate their CRO partner’s compliance to E8(R1) and E6(R3).

Every trial is unique; therefore, team members from all parties must use their experience to develop a holistic application of ICH and   regulatory guidance to understand the relevant data and take any necessary actions appropriately. In my experience, it all works best when strategists gather around a conference table to create a program design or project plan, while cross checking and managing risk from their respective functional angles.

If CROs are to maintain their status as trusted providers, they will have to adopt change management processes to thoroughly incorporate past and industry advances. I would recommend taking an all-inclusive review of internal processes to ensure they’re proactive in their intent and capable of accommodating current and future trial variabilities. In an ideal world, CROs would go on to pursue a cycle of continuous improvement in quality study management that includes proactive and reactive approaches to traceability, accountability, and data integrity.

When selecting their CRO partners, sponsors should take the necessary time to understand their chosen CRO’s approach to development, planning, and trial conduct. If the CRO in question has not fully embraced E6(R3) and E8(R1), the associated risks to their performance should be evaluated. It may even be necessary to establish a risk-sharing agreement as a guarantee that their process adoption won’t negatively impact the trial.  

In my view, the publication of ICH E8(R1) in October, and the upcoming E6(R3), represents an important step in our collective progress toward delivering quality outcomes in clinical trials. Becoming compliant with ever evolving international standards is a process that requires flexibility, forethought, and determination.

Adopting a logical, patient-focused, and quality-driven approach to planning and conducting clinical trials as outlined in the new guidelines will reward sponsors, CROs, sites, and patients. In the pursuit of excellence, we must all work together as a sector on setting new standards. Guidance of the kind offered in these two documents provides crucial support and motivation toward this noble end.

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About the Author
Sue Batchelor

Sue Batchelor is Director of Clinical Operations and Delivery Clinical Operations at Cmed Research, Horsham, UK

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