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The Value of Protocol Review

The Value of Protocol Review

One of our strategic customers recently invited me to review a draft protocol synopsis for a pivotal Phase III registration study. As the provider of the randomization and trial supply management (RTSM) solution  for the study, I relished the opportunity. Having reviewed thousands of protocols throughout my career, I knew that this was an ideal opportunity to consult with the clinical team to refine and optimize critical aspects of the study design. I’ve found that this proactive review process allows the team to set themselves up for success, fostering a spirit of partnership and collaboration with clinical technology solution partners.

The outcome of this review had far reaching implications. The synopsis described randomization of approximately 200 subjects into one of four treatment arms in an unusual treatment ratio. The randomization schema featured a numerous stratification and balancing criteria, including previous medication usage, and geographical region of study site. My first observation was that the treatment ratio was described in a way that would strongly imply a certain randomization block size. Disclosure of block size in a site facing protocol document is acknowledged as poor practice per ICH GCP regulations. There are negative consequences in terms of unblinding implications. The study biostatistician agreed that the protocol needed to articulate the randomization treatment ratio more optimally, and this triggered a revision of the protocol synopsis.

There were further outcomes of the review process. A few quick calculations led me to a speculation: does such a randomization schema run the risk of introducing an intolerable level of treatment imbalance within this study design, thus jeopardizing the planned analysis? I raised this speculation with the study biostatistician, who confirmed my hunch via formal randomization simulations. A dialogue followed where further options to mitigate against treatment imbalances were discussed. Bioclinica Trident RTSM features fully configurable turnkey options that can support any randomization scheme, including minimization methodologies described by Pocock and Simon (1975) . The option of using such a methodology was proposed to support this randomization scheme, but I openly consulted with the study biostatistician to explain some of the controversies associated with such an approach. This provided the study team plenty of food for thought.

This review process, coupled with further scientific considerations, ultimately resulted in the study randomization schema being dramatically simplified. The protocol was revised and the RTSM implementation cycle began via a formal kick off session.

Could a study protocol review by a RTSM consultant mitigate against substantial risks that jeopardize a critical study? Based on this evidence, I would say the answer is a resounding “YES!”….provided the clinical team engages and partners with solution vendors at a sufficiently early stage!



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