The Ripple Effect of Protocol Amendments in Medical Device Clinical Trials

Clinical trial protocols, or Clinical Investigation Plans (CIPs) in the case of medical devices, are foundational documents that define the structure and conduct of a study. As a Director of Clinical Operations in a Clinical Research Organization (CRO), I’ve encountered countless discussions about whether a protocol amendment is truly necessary. Each conversation underscores one reality: protocol amendments are a double-edged sword. While sometimes unavoidable, they bring substantial challenges that ripple through the trial’s ecosystem.

Over the years, our team has faced a wide variety of situations that required protocol amendments. These experiences have not only enhanced our expertise but also highlighted the importance of proactive planning and collaboration in minimizing disruptions. Let’s explore these complexities and considerations involved in making these decisions, particularly within the regulatory framework of the European Medical Device Regulation (MDR) and ISO 14155, the GCP for clinical studies of medical devices.

Why Protocol Amendments Happen

Protocol amendments are often necessitated by:

• Operational challenges: Addressing unforeseen difficulties in site performance, recruitment, or logistics. For example one clinical study we managed required an amendment because the rate of screen failures was much higher than expected—over 40%. This unexpected issue necessitated increasing the number of patients to be included to meet study goals. Looking back, I believe this situation may have been avoided if additional research had been conducted on the expected screen failure rates during the protocol design phase as well as a more careful phrasing with respect to the timing of subject enrolment.
• Scientific discoveries: New data that influences study objectives, endpoints, or eligibility criteria.
• Regulatory changes: Adjustments to ensure compliance with evolving standards like MDR or updates in ISO 14155, currently under revision. In the transition from MDD to MDR, for example, several of the clinical studies we were involved in required amendments when the MDR became effective, particularly to update safety reporting processes. This regulatory shift highlights the importance of staying ahead of legislative changes and proactively plan for their impact on ongoing trials.

Every amendment, however, should be critically evaluated to determine whether it is essential and justified at the specific point in time. The impact on timelines, budgets, systems, documents, and the people involved must be weighed carefully to avoid unnecessary disruptions.

Regulatory Hurdles

Amending a protocol is far from a simple process, especially in international, multi-center studies. Regulatory approvals from Competent Authorities (CAs) vary by region, each with its own timelines and requirements. Although the MDR aims to harmonize submissions across EU countries, the delayed implementation of the clinical module in EUDAMED means that submissions must still be handled separately for each country—a process that remains cumbersome and resource-intensive.

Additionally, a new ISO 14155 is expected to be released in 2025. This update will likely necessitate a review of protocols for ongoing trials to determine whether amendments are required to ensure compliance with the updated standard.

Training: A Continuous Cycle

Every protocol amendment necessitates training updates for both sponsor and site teams. Questions abound:

• Who needs training? Sponsors, investigators, coordinators, and other study staff.
• When and how should it be conducted? Efficient scheduling is critical to minimize downtime.
• What happens when different versions apply across sites? Managing version control and ensuring readiness for a new protocol is a delicate balance.

Informed Consent: A Bottleneck

Changes to a protocol often impact study participants, triggering a need for re-consent. In some cases, collecting re-consent can take months, particularly in multi-center trials or where participants are geographically dispersed. This raises critical questions:

• How do we ensure that participants are appropriately informed during the interim period?
• Can certain study activities proceed while awaiting re-consent, and what risks does this pose?

Impact on eCRF Systems

An amendment may necessitate changes to the electronic Case Report Form (eCRF), such as adding new fields or redoing data entry. In imaging-focused trials, additional functional assessments or other images may be required, further increasing complexity. Teams must:

• Adjust eCRF systems swiftly to accommodate changes.
• Manage the reconciliation of new and existing data without introducing errors.

The Domino Effect on Documentation

The protocol amendment is just the starting point. Downstream impacts include updates to:

• Informed Consent Forms (ICFs): Revisions must align with updated protocols.
• Tracking documents: Accurate version control becomes critical.
• Training records: Documentation must reflect that all relevant personnel have been trained on the new protocol.

Cost and Resource Considerations

The administrative, operational, and logistical implications of a protocol amendment are immense. Regulatory submissions, site coordination, re-training, and system updates all consume resources. The cumulative costs can be significant, both in terms of budget and timelines. Research showed that cost of a substantial amendment can be in the range of 147 to 520K euro, whereas almost half of them appear to be avoidable, So why do we keep doing this?

Key Takeaways for Managing Protocol Amendments

1. Think it through: Is the amendment necessary and justifiable? Assess the long-term benefits against short-term disruptions.
2. Collaborate early: Engage regulatory experts, site teams, and data managers to identify potential challenges and solutions.
3. Plan ahead: Anticipate the ripple effects across training, consent, and documentation.
4. Communicate consistently: Keep all stakeholders informed about timelines, requirements, and expected outcomes.
5. Optimize resources: Allocate sufficient time, budget, and personnel to handle the amendment’s demands.

Protocol amendments are an inevitable part of clinical research, especially in the dynamic field of medical devices. By carefully evaluating the need for changes and proactively managing their impacts, I believe we can mitigate disruptions and ensure that trials remain on track to deliver high-quality, reliable results.

Feel free to reach out should you have any questions or require support with the set-up or conduct of your clinical trial.

Petra de Jong
Arnhem, 06-JAN-2025