Ron Marks, PhD, serves as CSO and director of biostatistics and is a Clinipace Worldwide cofounder.

Thanks to everyone who tuned in to the webcast “Navigating Regulatory Biostatistical Requirements Throughout the Clinical Trial Lifecycle I recently hosted with my colleague Scott Miller, a biostatistician at Clinipace. During the presentation, we reviewed common statistical issues (during trial planning, conduct, analysis, and submission phases) and discussed potential approaches to address these issues.

As a result of a great turnout and many excellent follow-up questions, we decided to address a number of questions in a series of blog posts. In our first few posts, we’ll start with questions regarding trial planning. Check back next week for more great questions around regulatory biostatistical requirements during the trial conduct phase.

If you have any additional thoughts or related questions to ask our experts, please share your comments below.

Q: Will you please list some common protocol deviations?

A: As we discussed in the webinar, protocol deviations are defined as events that occur during your study that don’t go according to the protocol. When protocol deviations occur, they get graded during or at the end of the study to determine whether they are major or minor deviations. Major deviations are handled differently than minor deviations, and if you have a major protocol deviation, you are not part of the per-protocol analysis. All clients want to maximize their per-protocol population because that’s the population that followed the protocol. The more major protocol deviations that occur, the more subjects you lose from that analysis.

Typical protocol deviations include assessments or visits that occur outside of a protocol defined window of time. For example, a one-week window of post-treatment examinations might be seven days, plus or minus one day. A one-month window might be 30 days, plus or minus five to seven days. Sometimes some patients will just miss that window, which isn’t unusual. If it’s only by a day or two, it’s generally considered a minor deviation. Depending on how long it’s out of the window, it may be a major deviation and not allowed.

In addition, for many studies there’s a list of prohibited concomitant medications that patients should not be taking. However, inevitably some patients in a study will end up taking some of these prohibited concomitant medications. This is considered a protocol deviation, and the sponsor and CRO need to work together to decide whether or not it is a major protocol deviation that affects the efficacy or safety measurements being taken.

Mis-randomizations, or randomization errors, are generally considered major protocol deviations. Please note that a mis-randomization is any departure from the protocol-specified treatment allocation process; it does not matter if the subject ultimately received the correct treatment or not. There may be some cases that you could argue are minor, but most of them end up being major protocol deviations, which is why you want to minimize their occurrence. Some sites and sponsors don’t understand that those subjects would be excluded from the per-protocol population analysis, and it’s important to understand why.

Another interesting protocol deviation occurs when a study subject does not meet all study inclusion/exclusion criteria. This may happen if a site determines the subject meets all criteria, and then later discovers information that reveals one (or more) of the criteria was not met. In this situation, the sponsor and study personnel need to determine if this deviation should be major or minor. The other alternative is if a sponsor gives a site permission to enroll a subject that does not meet all the criteria. One common example is age. If a study requires subjects to be at least 50 years old, a sponsor might approve a 49-year-old if they meet other criteria. The situation would have to be one where the sponsor felt the failed criteria would not be critical for this particular subject.

Those are some of the most common types or most important types of protocol deviation, which, depending on whether they are major or minor deviations, can affect which analysis population they will be included in.

If you’re interested in learning more about Navigating Regulatory Biostatistical Requirements Throughout the Clinical Trial Lifecycle, be sure to listen to our webcast in its entirety. Check back soon for more questions regarding trial planning, conduct, and trial analysis/submission as well as the related eBook!

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