Protocol development is the ideal time to consider all potential issues and how they will be addressed rather than
skipping over them as theoretical abstractions and then planning to defer issue resolution until the time of analysis
or regulatory submission.
Trial Conduct
Even well-planned studies hit road bumps during trial conduct, such as misrandomizations and serious protocol
deviations. When issues occur during study conduct, it is best to address them promptly and to provide
additional training, if warranted, to prevent more occurrences during the remainder of the study.
EXAMPLE
With slow enrollment, it can be tempting to modify the eligibility criteria to
increase the likelihood of finding suitable participants.
Clinipace is managing the full trial lifecycle for a phase III pivotal trial to demonstrate the safety
and efficacy of a client’s product. Subject enrollment was slower than desired, and the client was
considering modifying the eligibility criteria to widen the pool of potential participants by lowering
the body mass index (BMI) for eligibility from 35 kg/m2 (obese) to 30 kg/m2 (overweight). Clinipace
Biostatistics provided the client with the potential statistical and regulatory implications of such a
change; for example, the FDA might view the patient population as no longer being homogenous.
Clinipace Biostatistics suggested that if the criteria were adjusted, additional analyses could be prespecified based on high and low BMI to verify that they responded to the treatment in the same way.
Based on this advice, the client could make an informed decision about the change and address
potential regulatory concerns in advance.
EXAMPLE
Misrandomization can easily occur during the conduct of a trial.
During another phase III pivotal trial to demonstrate noninferiority of the product to an existing
approved product, for which the full trial lifecycle was managed by Clinipace, one of the sites
inadvertently provided a subject with the wrong study kit, therefore misrandomizing that subject.
Clinipace Biostatistics was able to provide a report to the sponsor summarizing the regulatory
perspective on the most appropriate way to handle the situation. Additionally, Clinipace’s Site
Management Services group provided refresher training to all sites on proper kit provision to
subjects to prevent future recurrence.
In a standard clinical trial design, the trial recruits subjects, and once the target enrollment is reached, the final
analysis is conducted. For a variety of reasons, trial sponsors sometimes conduct interim analyses, where the
accumulating trial data are formally examined prior to the end of the study. There are multiple reasons sponsors
conduct such analyses:
• To determine whether the initial target sample size needs to be revised (sample size re-estimation [SSR])
• To determine if the trial is unlikely to demonstrate a clinically and statistically significant treatment
effect (futility analysis)
• To determine if the current results are sufficiently supportive to justify stopping the trial before
reaching the final analysis (efficacy analysis)
• To document a potential negative safety issue
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