Benefit Risk Assessment: Case Studies

Organizers: Richard Payne (Lilly), Yeh-Fong Chen (FDA)
Chair: Richard Payne (Lilly)
Vice Chair: Rakhi Kilaru (PPD)

Speakers:
Michael Sonksen (Lilly)
Bennett Levitan (J&J)
Bill Wang (Merck)

Discussants:
Saurabh Mukhopadhyay (Abbvie)
Lan Huang (FDA)

Abstracts:

Title: A Bayesian Benefit Risk Assessment
Speaker: Michael Sonksen (Lilly)

Benefit risk assessments are conducted throughout the drug development process to ensure that the expected benefits outweigh the potential risks of a medicine for patients. Leveraging external data in benefit risk assessments is helpful as it can help fill in the gaps of knowledge in early phase development and provide a landscape of benefit risk profiles from approved medicines. External data can come from publications from drugs with similar mechanism of action, evidence within the same indication, or even expert elicited priors. The Bayesian approach is a natural framework to account for various external data sources and combine them with the current data. In this talk, we will share a joint Bayesian model which takes into account the totality of evidence from multiple safety and efficacy outcomes while incorporating available external data. We will work through potential ways to setup a Bayesian benefit risk assessment to be used throughout drug development. This is a joint work with JuAn Wang and Haiqing You.

Title: Structured Benefit-Risk Assessment and Patient Preference Studies for Esketamine in Treatment Resistant Depression
Speaker: Bennett Levitan (Janssen)

Treatment resistant depression (TRD) is a form of major depressive disorder in which patients fail to respond to two or more antidepressants given with adequate dose, duration and compliance. TRD is associated with considerable disease burden, reduced quality of life and higher rates of suicide attempts than in major depressive disorder that responds to antidepressants. The esketamine program studied the efficacy and safety in TRD of esketamine nasal spray, an enantiomer of ketamine, given with an oral antidepressant. The program included multiple pivotal induction studies with different dosing regimens and a long-term maintenance study. During the development program, a structured benefit-risk (B-R) framework approach was developed to support benefit-risk assessment in regulatory submissions. Because of the novel nature of the treatment and the potential long-term risks seen in ketamine abuse, a patient preference study was developed. This preference study was conducted in both clinical trial subjects and subjects from an on-line panel to assess the importance of different trial endpoints to patients and what benefit-tradeoffs patients would consider acceptable. This B-R assessment and these preference studies were included in the regulatory submission and FDA advisory committee presentation. In this talk, we review the development of the structured B-R framework and patient preference studies, the results of these analyses, and how they were integrated into the clinical protocol and regulatory submission to support a positive B-R assessment for esketamine.

Title: Aggregate Safety Assessment Planning (ASAP) and Benefit-Risk Assessment Planning (BRAP)
Speaker: Bill Wang (Merck)

This presentation will give an overview of two key task forces by the ASA-DIA Interdisciplinary Safety Working Group: Aggregate Safety Assessment Planning (ASAP) and Benefit-Risk-Assessment-Planning (BRAP). We will share the intention, the industry survey, the key deliverables from these initiatives. Together the ASAP and BRAP provide structured approaches to proactively plan the holistic and iterative evaluation of product safety and benefit-risk profile.