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IQ DILI Casuality Assessment Working Group Public Call for Participation

IQ DILI Casuality Assessment Working Group Public Call for Participation

August 17, 2020

IQ DILI Casuality Assessment Working Group Public Call for Participation

Co-Chairs: John Caminis, Sanofi and Klaudia Steplewski, GlaxoSmithKline

Background, Rationale and Project Details

Drug-induced liver injury (DILI) is a leading cause of acute liver failure and therefore a significant concern for patients, physicians, researchers and regulators.  It is one of the most frequent causes of post-approval drug withdrawal and attrition in drug development. The biggest challenge with assessment of DILI is establishing causal association between the liver injury and the drug since the evidence is usually circumstantial, subjective and with varying levels of confidence.  Positive rechallenge has been associated with a number of drugs (i.e. antimicrobials, or oncology therapeutics) and has higher risk of more severe liver injury following re-initiation of the drug including death.  Although it contributes to the overall evidence for suspected DILI, the risk of re-exposure has not been well studied since rechallenge is not allowed in most clinical studies. In public domain there is very limited data with only few prospective studies published.  Moreover, published regulatory and expert guidelines in general do not recommend rechallenge after suspected DILI and therefore do not address issues related to 1) the criteria (i.e. benefit risk, patient populations etc..) when rechallenge may be considered,  2) patient awareness of potential risks of reintroducing drug, 3) patient monitoring and management following the rechallenge including recommendation for dose modifications.  Therefore, lack of sufficient data from prospective controlled clinical trial contributes to the overall knowledge gap in understanding the risk factors for positive rechallenge and outcomes following rechallenge.  The Causality Assessment Working Group has finalized consensus paper addressing best practices pertaining to causality assessment in DILI that included brief references to the role of drug rechallenge and utility of liver biopsy in causality assessment. To complement this manuscript, the group is now initiating work on two manuscripts: one on best practices and guidelines for drug rechallenge in clinical development and in clinical practice and second manuscript focusing on the role of biopsy in causality assessment in DILI and best practices and guidelines for liver biopsy in clinical development and in clinical practice. These projects require strong expertise in hepatology as well as knowledge and experience in DILI and in drug development.  A non-member participant with the necessary background, expertise and experience in these fields would be an invaluable addition to our working group. In addition, a strong background in drug safety and the regulatory requirements related to clinical trials and drug registration would enhance the group’s capability to interpret the available data and reach consensus with regulatory and academic participants.

Qualifications (all are necessary)

• Training and clinical experience in clinical hepatology
• Participation during academic career in interventional clinical trials in patients with liver diseases
• Experience with authoring scientific publications in the field of clinical hepatology and DILI
• Experience with acute, chronic and progressive liver diseases which might be confounders in potential cases of DILI
• Experience in pharmaceutical industry doing registration grade clinical trials for new drugs with experience in monitoring for, diagnosing, and managing potential DILI during these clinical trials.
Respondents please note this is a volunteer role.

Expected Duration of Engagement

As discussed above, the IQ DILI Causality Assessment Woking Group (WG) is developing two manuscripts through a series of working meetings. The ultimate goal is to publish these manuscripts in peer-reviewed journals. Final publication of these manuscripts is expected in 2-3 years. Selected volunteers will remain as a working member of the team through the final publication of these manuscripts, at which time, membership will be re-evaluated based on the needs of the Causality Assessment WG.

Please click here to send your response, including a current CV, by 03 SEPTEMBER 2020.