How Aggregate Safety Assessment Planning Supports Investigational New Drug Safety Reporting Decisions.

In June 2021, FDA released a Draft Guidance on Sponsor Responsibilities for IND Safety Reporting and cited components of a recommended Safety Surveillance Plan (SSP). To meet the expectations of the 2021 FDA guidance, sponsors should document their plan for aggregate safety assessment. The Drug Information Association-American Statistical Association Interdisciplinary Safety Evaluation scientific working group has proposed an Aggregate Safety Assessment Plan (ASAP) that addresses this recommendation. The 2021 FDA guidance also discusses potential strategies for unblinded review of safety data from ongoing studies by an independent Assessment Entity, which could occur via planned periodic evaluations or "triggered" reviews based on blinded data assessments. The Assessment Entity reviewing unblinded data makes recommendations as to whether the threshold has been met for submission of an aggregate IND safety report. In this paper, we discuss how the ASAP supports IND aggregate safety reporting decisions, including elements to be included in a proposed SSP appendix to the ASAP. In addition, the authors advocate for the benefits of developing a charter (or specific section of the Data Monitoring Committee charter, if applicable) that describes the responsibilities and conduct of the Assessment Entity. With these components in place, study sponsors will meet the objective of having clearly defined processes for the monitoring of clinical trial safety data in aggregate and making IND safety reporting decisions.

Value and Implementation of the Aggregate Safety Assessment Plan.

Aggregate safety assessment involves evaluation of the totality of safety data to characterize the emerging safety profile of a product. The Drug Information Association-American Statistical Association Interdisciplinary Safety Evaluation scientific working group recently published an approach to developing an Aggregate Safety Assessment Plan (ASAP). Creation of an ASAP facilitates a consistent approach to safety data collection and analysis across studies and minimizes important missing data at the time of regulatory submission. A critical aspect of the ASAP is identification of the Safety Topics of Interest (STOI). The STOI, as defined in the ASAP, comprises adverse events (AEs), which have the potential to impact the benefit: risk profile of a product and typically require specialized data collection or analyses. While there are clear benefits to developing an ASAP for a drug development program, multiple concerns may be encountered with implementation. This article uses the examples of two STOIs to demonstrate the benefits and efficiencies gained with implementation of the ASAP in safety planning as well as in optimally characterizing the emerging safety profile of a product.

Aggregate Safety Assessment Planning for the Drug Development Life-Cycle.

The Program Safety Analysis Plan (PSAP) was proposed previously as a tool to proactively plan for integrated analyses of product safety data. Building on the PSAP and taking into consideration the evolving regulatory landscape, the Drug Information Association-American Statistical Association (DIA-ASA) Interdisciplinary Safety Evaluation scientific working group herein proposes the Aggregate Safety Assessment Plan (ASAP) process. The ASAP evolves over a product's life-cycle and promotes interdisciplinary, systematic safety planning as well as ongoing data review and characterization of the emerging product safety profile. Objectives include alignment on the safety topics of interest, identification of safety knowledge gaps, planning for aggregate safety evaluation of the clinical trial data and preparing for safety communications. The ASAP seeks to tailor the analyses for a drug development program while standardizing the analyses across studies within the program. The document is intended to be modular and flexible in nature, depending on the program complexity, phase of development and existing sponsor processes. Implementation of the ASAP process will facilitate early safety signal detection, improve characterization of product risks, harmonize safety messaging, and inform program decision-making.

Effects of hyperfibrinogenemia on vasculature of C57BL/6 mice with and without atherogenic diet.

OBJECTIVE: Elevated fibrinogen is correlated with severe atherosclerosis, as defined by the occurrence of ischemic events, but the mechanistic basis for this correlation remains unknown. To study this relationship, we examined spontaneous and diet-induced atherosclerosis in transgenic mice with hyperfibrinogenemia (elevated fibrinogen). METHODS AND RESULTS: Normal and transgenic mice were fed either an atherogenic diet or simple breeder chow. We measured plasma fibrinogen levels and identified an age-dependent and diet-dependent increase in fibrinogen. After 8 to 12 months, aortic sections were prepared and stained, and lipid-containing lesions were counted, measured, and assessed for maturity. Lipid-filled deposits appeared spontaneously in a small number of mice on breeder chow; typical fatty streak-type lesions appeared in almost all of the diet-fed animals. Morphometric analysis showed that neither the number nor the size of lesions was influenced by either fibrinogen level or genotype. CONCLUSIONS: Our data showed that neither fibrinogen concentration nor genotype had a statistically significant effect on the initiation, initial growth, or early progression of atherosclerotic lesions.