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In June 2021, FDA released a Draft Guidance on Sponsor Responsibilities for IND Safety Reporting and cited components of a recommended Safety Surveillance Plan (SSP).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.

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 Bayesian method for safety signal detection in ongoing blinded randomised controlled trials.

Sponsors have a responsibility to minimise risk to participants in clinical studies through safety monitoring. The FDA Final Rule for IND Safety Reporting requires routine aggregate safety evaluation, including in ongoing blinded studies. We are interested in estimating the probability that the true adverse event rate in the experimental arm exceeds that in the control arm.

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.

Conversion to brivaracetam monotherapy for the treatment of patients with focal seizures: Two double-blind, randomized, multicenter, historical control, Phase III studies.

Brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle protein 2A, is a new antiepileptic drug (AED) approved for monotherapy (in the USA) and adjunctive treatment of focal (partial-onset) seizures in adults, at a dose range of 50-200 mg/day taken in two equal doses, with a recommended starting dose of 100 mg/day. Two Phase III, randomized, double-blind, multicenter, historical-controlled, conversion-to-monotherapy studies (N01276, NCT00698581; N01306, NCT00699283) were conducted to evaluate the efficacy, safety, and tolerability of conversion to BRV 50 mg/day monotherapy in adults with uncontrolled focal seizures. Patients aged 16-75 years, with 2-40 focal seizures per 4 weeks during an 8-week baseline, and on stable doses of 1-2 AEDs were enrolled.

Adjunctive lacosamide for focal epilepsy: an open-label trial evaluating the impact of flexible titration and dosing on safety and seizure outcomes.

To evaluate the safety and effectiveness of lacosamide in a real-life setting with the use of a flexible dose titration schedule and individualised maintenance doses up to the maximum approved dose of 400 mg/day. Adults with a diagnosis of focal seizures, with or without secondary generalization, were enrolled in this open-label Phase IV trial (NCT01235403). Lacosamide was initiated at 100 mg/day (50 mg bid) and uptitrated over a 12-week period to 200, 300 or 400 mg/day, based on safety and seizure control.

Levetiracetam extended release for the treatment of patients with partial-onset seizures: A long-term, open-label follow-up study.

This was an open-label study (N01281 [NCT00419393]) assessing the long-term safety of extended-release levetiracetam (LEV XR) in patients with partial-onset seizures (POS); the study was a follow-up to a double-blind, randomized, historical controlled, multicenter, conversion to monotherapy study (N01280 [NCT00419094]). Eligible patients initially received LEV XR 2000 mg/day; dose adjustments and the addition of other antiepileptic drugs (AEDs) were permitted. Overall, 190 patients were enrolled, 189 (99.

Long-term adjunctive lacosamide treatment in patients with partial-onset seizures.

Objective: To evaluate long-term (up to 5.5 years) safety, seizure reduction, and maintenance of efficacy of the antiepileptic drug (AED) lacosamide as adjunctive treatment in an open-label extension trial (SP774; ClinicalTrials.gov: NCT00515619).

Safety and efficacy of adjunctive lacosamide among patients with partial-onset seizures in a long-term open-label extension trial of up to 8 years.

Long-term (up to 8 years of exposure) safety and efficacy of the antiepileptic drug lacosamide was evaluated in this open-label extension trial (SP615 [ClinicalTrials.gov identifier: NCT00552305]). Patients were enrolled following participation in a double-blind trial or one of two open-label trials of adjunctive lacosamide for partial-onset seizures.

Levetiracetam extended release conversion to monotherapy for the treatment of patients with partial-onset seizures: a double-blind, randomised, multicentre, historical control study.

This double-blind, randomised, multicentre, conversion to monotherapy, historical control study (N01280; NCT00419094) evaluated the efficacy, safety and tolerability of levetiracetam extended release (LEV XR) 2000mg/day once daily for the treatment of patients with partial-onset seizures compared with a historical control. Patients aged 12-75 years with 2-40 partial-onset seizures per 4 weeks, taking 1-2 antiepileptic drugs (AEDs) and receiving a stable dosage for ≥4 weeks prior to screening were randomised in a 3:1 ratio to LEV XR 2000 or 1000 mg/day. The study comprised baseline (8 weeks), LEV XR up-titration (2 weeks), baseline AED tapering (6 weeks), LEV XR monotherapy (10 weeks), and entry into open-label follow-up study or down-titration (1 week).

Long-term safety and efficacy in patients with uncontrolled partial-onset seizures treated with adjunctive lacosamide: results from a Phase III open-label extension trial.

Purpose: To evaluate the long-term (up to 5 years exposure) safety and efficacy of lacosamide as adjunctive therapy in patients with uncontrolled partial-onset seizures taking one to three concomitant antiepileptic drugs (AEDs) in open-label extension trial SP756 (NCT00522275).

Methods: Patients who completed the double-blind trial SP754 (NCT00136019) were eligible to participate in this open-label extension trial (SP756). At the conclusion of trial SP754, patients had transitioned to lacosamide 200 mg/day.

Shifting gears: jump-start interdisciplinary patient care.

Effective patient care planning and education requires an interdisciplinary approach that accelerates collaborative practice and timely patient outcomes. Is it time for you to head in this direction?

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.