Theradex’s extensive experience with early phase oncology clinical trials provides a unique opportunity to help sponsors utilize a Quality by Design approach. A thorough Risk Assessment is the first step in Theradex’s Quality by Design (QbD) and Risk Based Monitoring (RBM) approach. The Risk Assessment Plan not only addresses items in the protocol, which may be lacking a QbD approach, but also outlines Theradex’s suggestions regarding the appropriateness of implementing RBM into the clinical study.
Theradex routinely requests an early review of the draft protocol or study synopsis to identify potential risks in the study design that may result in slow patient accrual, poor quality data, site compliance difficulties or data that does not support the study objectives. Examples of such risks include excessive PK sampling requirements or ill-considered correlative assays, collection of inconsequential data points, misunderstanding site capabilities or their standard clinical practice, as well as underestimating necessary site training.
Protocol development is the first step in the clinical portion of QbD. The protocol describes the study design for all investigators who are participating in the study. To optimize the protocol compliance and increase the output quality of the clinical study, Theradex requires appropriate investigator input prior to protocol finalization. The goals of investigator input include: 1) review of inclusion/exclusion criteria to ensure that the interpretation of the criteria are as intended by the Sponsor, the criteria are not unnecessarily restrictive and are appropriate to the study so that accrual goals can be met, 2) review of the timing, frequency and appropriateness of any clinical procedures and follow-up visits, 3) review of study treatment procedures to assure that pharmacy and nursing practice logistics are considered appropriately. By discussing the study design with investigators prior to launch, Theradex seeks to avoid potential impediments to study accrual and minimize protocol deviations and site compliance problems. In addition to protocol review by the Sponsor, Theradex medical monitor, and principal investigator to optimize study design, the Theradex data management group also conducts a protocol review to ensure that an optimized dataset will be collected. Minimizing data output errors occurs by ensuring only essential data is to be collected. Theradex defines essential data as data that is relevant and critical to safety and effectiveness endpoints, meets all guidance recommendations with a “less is more” approach, and avoids duplicate data entry.
Ongoing risk assessment occurs throughout the study on a quarterly basis. These risk assessment discussions take place with the Sponsor during the quarterly contract review meetings. Issues related to previously identified risks are discussed and solutions provided. When a new risk is identified, it is added to the Risk Assessment Plan and a remediation plan is put in place. Any revisions to study plans, binders or re-training that are necessary as a result of the newly identified risk are implemented as soon as possible.
The Risk Assessment Plan and ongoing risk assessments also dictate whether the study is an appropriate candidate for “risk-based monitoring”. While the FDA and EMA guidances suggest that RBM is not suitable for most early phase oncology trials, Theradex is extremely experienced in the realm of RBM and has been performing RBM for the National Cancer Institute’s early phase clinical trials since 1985. Along with the NCI experience, Theradex continues to analyze each industry study to assess the suitability of RBM and currently utilizes the process in several Phase II industry trials.