Protocol Amendments & the Domino Effect on Study Conduct (2024)

Have you ever thought about the amount of time it takes to implement changes to your Study after a protocol amendment gets approved? This can take weeks, or even months, of configuration, testing and validation, retraining and communication, to get all of your Site’s up to speed on the latest updates.

To give us a quantifiable number, Tufts Center for the Study of Drug Development (Tufts CSDD) continues to do research on the impact of protocol amendments, helping us realize the time, cost and resources behind implementing an amendment. According to their latest follow-up study conducted by Getz et al., since 2015 the prevalence of protocols with at least one amendment in phases I-IV has increased substantially, from 57 to 76%, and the average number of amendments per protocol has increased 60% to 3.3, up from 2.1. Phase I and III protocols saw the highest increases in the mean number of amendments implemented per protocol. Compared to before, a much higher percentage of these amendments (77%) were deemed unavoidable with regulatory agency requests and changes to the study strategy as the top reasons cited for amending a protocol.

Shockingly, the total average duration to implement an amendment has nearly tripled during the past decade. The time from identifying the need-to-amend to last oversight approval now takes an average of 260 days, and the mean duration during which investigative sites operate with different versions of the clinical trial protocol spans 215 days (Getz et al., 2022).

These amendments can be due to various factors, including regulatory requirements, new safety information, or changes in trial design or operational strategies. The frequency and number of amendments can vary depending on the complexity and phase of the trial, the therapeutic area, and the specific regulatory environment. For example, a Phase III oncology study would have a lot more amendments than a Phase I dermatology study.

So can we avoid protocol amendments? Or even get ahead of them before they become necessary?

Even though they are nearly inevitable, here are a few things you can do to reduce the number of protocol amendments over the course of your next trial:

1. Feasibility Assessments - We’re not at Site feasibility yet, we’re talking about Trial feasibility. Ensure enough pre-trial research has been done to ensure the protocol is realistic and can be executed across different sites and populations. Before implementing the full-scale study, consider running small pilot studies to identify additional risks or issues.
2. Thorough Planning and Design - Invest adequate time and effort into protocol development from the beginning. This includes anticipating risks, incorporating flexibility, and getting key stakeholders input early on.
3. Adaptive and Flexible Design - As mentioned above, incorporating flexibility into the protocol where appropriate, can allow for predefined adjustments to be made during the trial, without requiring a formal amendment. This could look like starting with a broader inclusion criteria to allow for informal amendments to expand the eligibility criteria later on.
4. Clear and Detailed Protocol Documentation - Adaptive and flexible, does not mean we should not be clear and concise in the protocol. There should be no room for misinterpretations, as this could necessitate amendments. Defining processes and procedures in detailed SOPs will maintain consistency and clarity during trial execution.
5. Effective Communication and Training - By providing a comprehensive training for all study personnel, it ensures they understand the protocol and will adhere to it. Record training sessions when possible so they can be accessed later on for reference. Follow-up or refresher trainings should always be available to study staff. Make yourself available to site staff and maintain regular communication so that they feel comfortable coming to you with issues or questions before it turns into a full on protocol deviation.
6. Real-Time Data Monitoring - Site monitoring and real-time data collection will allow you to quickly identify and address emerging issues without the need for amendments. Go a step further and implement risk-based monitoring to focus on areas of high-risk, reducing the need for unnecessary protocol amendments.
7. Regulatory Engagement - Engage with regulatory agencies early and throughout the trial to ensure alignment on the protocol, reducing the likelihood of regulatory-requested amendments. Before submission, seek advice via pre-submission meetings and reviews to preemptively address regulatory concerns.
8. Utilize Advanced Technologies - Technology can help you stay on top of your study's operations, facilitate communication, data collection and analysis, and stay ahead of protocol amendments.

Cloudbyz Solutions

By using the Cloudbyz EDC, and its user-friendly, cloud-based features like form versioning and real-time communication to Sites, reduce the time to implement protocol amendments in your EDC, and get all of your sites trained on the latest protocol faster. Not to mention, the Cloudbyz EDC meets all of the essential regulatory compliance requirements such as FDA- 21 CFR Part 11, GCP, GAMP5, HIPAA, and EU- GDPR.

Expand your Cloudbyz footprint and use the EDC in conjunction with our CTMS for a seamless remote monitoring experience. Enable your CRAs to complete their visit reports and review data all in one place, allowing for real-time collaboration and communication.

To learn more about Cloudbyz products, contact info@cloudbyz.com