Aggregate Safety Assessment Planning for the Drug Development Life-Cycle

Hendrickson, Barbara A.; Wang, William Yang; Ball, Greg; Bennett, Dimitri; Bhattacharyya, Amit; Fries, Michael; Kuebler, Juergen; Kurek, Raffael; McShea, Cynthia; Tremmel, Lothar

doi:10.1007/s43441-021-00271-2

Cited by 11 publications

(3 citation statements)

References 28 publications

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“…Our survey suggests that currently planning and aligning safety and bene t-risk assessment is not commonly done by the drug or medical device companies, though safety planning, for example with a Program Safety Analysis Plan (PSAP) [21] or the further extended Aggregate Safety Assessment Plan (ASAP) [22] is done by most of the companies questioned. Therefore, we suggest that future progress might be stimulated by a consistent integrated plan for safety and bene t-risk that facilitates discussion, speci es the metrics of the sBRA, documents decision-making, implements a rationale and enables the communication of the bene t-risk balance.…”

Section: Discussionmentioning

confidence: 99%

A Survey to Assess the Current Status of Structured Benefit-Risk Assessment in the Global Drug and Medical Device Industry

Gebel,

Renz,

Rodriguez

et al. 2024

Ther Innov Regul Sci

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BackgroundThis industry survey was conducted to gain insight into the ways structured Bene t-Risk assessment (sBRA) of medical products is approached across drug or medical device developing companies, including frameworks and methods that are currently used and areas where future work is being planned. MethodsA survey containing 28 questions covering ve key areas of sBRA was set-up and shared with representatives from the participating companies. Each company was asked to complete a single survey response including inputs across the company's multidisciplinary key representatives involved in bene t-risk assessment. ResultsOf the 26 participating companies, 21 are conducting sBRA. Qualitative frameworks were used by almost every company (19), while only 12 have used a quantitative method. Many companies have sBRA training (17), document templates (16), Standard Operating Procedures (SOPs)/checklists (13), and /or best practice manuals/examples (12) available. Software tools (15/26) and BR planning documents (11/26) were identi ed as areas into which many companies intend to put effort. ConclusionsThe industry survey con rmed a wide usage of sBRA by many companies involved in research and development.Nevertheless, sBRA is evolving and several future opportunities like the implementation of visualization tools were identi ed by the representatives of the pharmaceutical companies. Finally, challenges like the cross-functional comprehension of the added value of sBRA are still seen.

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Section: Discussionmentioning

confidence: 99%

A Survey to Assess the Current Status of Structured Benefit-Risk Assessment in the Global Drug and Medical Device Industry

Gebel,

Renz,

Rodriguez

et al. 2024

Ther Innov Regul Sci

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“…2 Other events that are expected to occur in the population regardless of treatment received, referred to as anticipated events, require an aggregate analysis to assess if the risk of the event is elevated due to receipt of treatment. A process for planning multi-disciplinary safety monitoring that could support the recommendations of the FDA guidelines is discussed by Hendrickson et al 3 As a component of the ongoing safety review, the FDA guideline recommends evaluating blinded study event rates versus background event rates for events that require an aggregate analysis to assess causality. With this approach, if the blinded overall rate is substantially higher than the background rate in the population, the event could be escalated for further evaluation by the SMT and potentially assessed by a separate safety assessment committee via an unblinded aggregated analysis.…”

Section: Introductionmentioning

confidence: 99%

“…Other events that are expected to occur in the population regardless of treatment received, referred to as anticipated events, require an aggregate analysis to assess if the risk of the event is elevated due to receipt of treatment. A process for planning multi‐disciplinary safety monitoring that could support the recommendations of the FDA guidelines is discussed by Hendrickson et al 3 …”

Section: Introductionmentioning

confidence: 99%

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

Brock

Chen

Ho³

et al. 2022

Pharmaceutical Statistics

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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. We developed a Bayesian approach that specifies an informative meta‐analytic predictive prior on the event probability in the control arm and an uninformative prior on that in the experimental arm. We combined these priors with a mixture likelihood that considers each patient in the ongoing blinded study may belong to the experimental or control arm. This allowed us to estimate the quantity of interest without unblinding. We evaluated our method by simulation, pairing scenarios that differed only in whether a safety signal was present or missing, and quantifying the ability of our model to discriminate using signal detection theory. Our approach shows benefit. It detects safety signals more reliably with greater sample sizes and for common rather than rare events. Performance does not deteriorate markedly when historical studies exhibit heterogeneous hazards or non‐constant hazards. Our method will allow us to monitor safety signals in ongoing blinded studies with the goal of earlier identification and risk mitigation. Our method could be adapted to use informative priors on both arms or predictive covariates where pertinent data exist. We stress that ongoing safety monitoring should involve a multi‐disciplinary team where statistical methods are paired with medical judgement.

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