Overview of Causality Assessment for Drug-Induced Liver Injury (DILI) In
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Drug Safety https://doi.org/10.1007/s40264-021-01051-5 LEADING ARTICLE Overview of Causality Assessment for Drug‑Induced Liver Injury (DILI) in Clinical Trials Juliana Hey‑Hadavi1 · Daniel Seekins2 · Melissa Palmer3,13 · Denise Cofey2 · John Caminis4 · Sandzhar Abdullaev2 · Meenal Patwardhan5 · Haifa Tyler6 · Ritu Raheja5 · Ann Marie Stanley7 · Liliam Pineda‑Salgado6 · David L. Bourdet8 · Raul J. Andrade9 · Paul H. Hayashi10 · Lara Dimick‑Santos11 · Don C. Rockey12 · Alvin Estilo6 Accepted: 1 February 2021 © The Author(s) 2021 Abstract Causality assessment for suspected drug-induced liver injury (DILI) during drug development and following approval is chal- lenging. The IQ DILI Causality Working Group (CWG), in collaboration with academic and regulatory subject matter experts (SMEs), developed this manuscript with the following objectives: (1) understand and describe current practices; (2) evaluate the utility of new tools/methods/practice guidelines; (3) propose a minimal data set needed to assess causality; (4) defne best practices; and (5) promote a more structured and universal approach to DILI causality assessment for clinical develop- ment. To better understand current practices, the CWG performed a literature review, took a survey of member companies, and collaborated with SMEs. Areas of focus included best practices for causality assessment during clinical development, utility of adjudication committees, and proposals for potential new avenues to improve causality assessment. The survey and literature review provided renewed understanding of the complexity and challenges of DILI causality assessment as well as the use of non-standardized approaches. Potential areas identifed for consistency and standardization included role and membership of adjudication committees, standardized minimum dataset, updated assessment tools, and best practices for liver biopsy and rechallenge in the setting of DILI. Adjudication committees comprised of SMEs (i.e., utilizing expert opinion) remain the standard for DILI causality assessment. A variety of working groups continue to make progress in pursuing new tools to assist with DILI causality assessment. The minimum dataset deemed adequate for causality assessment provides a path forward for standardization of data collection in the setting of DILI. Continued progress is necessary to optimize and advance innovative tools necessary for the scientifc, pharmaceutical, and regulatory community. 1 Introduction organization addressing scientifc and technical aspects of drug development and comprises over 30 pharmaceutical The IQ drug-induced liver injury (DILI) Initiative was and biotechnology companies. The IQ-DILI Initiative is an launched in June 2016 within the International Consortium afliate of the IQ Consortium, comprised of 17 IQ mem- for Innovation and Quality in Pharmaceutical Development ber companies, focused on establishing best practices for (also known as the IQ Consortium) to reach consensus and monitoring, diagnosing, managing, and preventing DILI. propose best practices on issues surrounding DILI. The This review paper is based on an extensive literature review IQ Consortium is a leading science-focused, not-for-proft and cross-pharmaceutical industry survey data; the consen- sus and fndings are achieved through carefully structured discussions between IQ DILI members as well as academic The views expressed are those of the authors and do not and regulatory experts. necessarily represent the position of, nor imply endorsement from, Causality assessment for suspected DILI is a major chal- any of the companies, the US Food and Drug Administration or lenge during drug development and following approval. the US Government. Given the intricacies of determining causality from DILI due * Juliana Hey-Hadavi to a suspected drug, industry, regulators, and academia con- [email protected] tinue to explore this complex topic. The diagnosis of DILI * Alvin Estilo is challenging given the multitude of clinical variables that [email protected] must be considered, the temporal relationship of the injury Extended author information available on the last page of the article to the administration of the suspect drug, the clinical course Vol.:(0123456789) J. Hey-Hadavi et al. • Understand and describe the current state of DILI causal- Key Points ity assessment. • Evaluate the utility of new tools/methods/practice guide- There is a need for a uniform approach to causality lines. assessment in DILI, which is expected to include novel • Recommend a proposal for a minimal data set needed to methodology and/or an update of existing tools and to assess causality. enhance reliability, reproducibility, and completeness of • Defne best practices for causality assessment as they DILI assessment in clinical trials. relate to DILI. When establishing an adjudication committee, a mini- • Promote a more structured and universal approach to mum of three experienced experts in the feld of clini- DILI causality assessment. cal hepatology/DILI should be used to ensure clarity of decision making in the assessment. 2 Strategy Rechallenge and liver biopsy should be considered when the beneft for the patient of continued treatment with the The IQ DILI CWG applied several strategies to gain bet- suspect drug exceeds risk. ter insight into current practice of causality assessment for The establishment of a minimum data set for causality DILI, including a review of the literature (ROL) and admin- assessment in clinical trials and in the post-marketing istration of a survey (hereafter called ‘the survey’). The environment is recommended to assist with the assess- data and information generated from ROL and the survey ment and diagnosis of DILI. passed through a number of structured discussions during dedicated face-to-face (F2F) meetings with subject matter experts (SME) with academic and regulatory backgrounds. The ROL, survey, and interaction with SMEs assisted the CWG with development of recommendations and guidance of abnormal liver tests, the presence, absence, or potential to industry, academia, and health authorities. interactions of concomitant medications, knowledge of the The survey was distributed to the IQ DILI member phar- suspect drug’s propensity to cause hepatotoxicity and, per- maceutical companies and results were reviewed by the haps most importantly, the elimination of alternate potential CWG. The survey provided information on up-to-date prac- causes of liver injury [1, 2]. Seeking an expert opinion to tices and trends of causality assessment in pharmaceutical diagnose DILI is the ‘gold-standard’ approach [3] used by companies. Advice and insights from leading SMEs amongst pharmaceutical companies and regulatory agencies to both the CWG and external SMEs played an important role in identify or confrm DILI cases and assess a drug’s hepato- gathering feedback. toxic potential, especially during clinical drug development. However, lack of defned criteria leading to subjectivity in 2.1 Review of Literature (ROL) drawing defnitive conclusions, and occasional lack of expert consensus have been viewed as limitations [4]. Additional An initial search was performed in PubMed and Google challenges in both the clinical trial and post-marketing set- Scholar on “drug safety causal assessment for liver injury.” ting include missing data and collection of an appropriate The search string was entered without quotes, so terms were minimal data set to enable adequate assessment of causal- search combinatorically. Additional ad-hoc searches were ity for DILI. Over the years, other attempts at standardized conducted pertaining to related keywords (i.e., hepatoxicity, approaches and tools (e.g., RUCAM; Maria and Victorino drug toxicity, hepatic adverse events), principal investiga- method) have been met with limited success and uptake and tors, and references cited within identifed articles. Titles have been criticized, especially regarding their utility in the and abstracts were reviewed by the IQ DILI Secretariat to setting of clinical trials. A structured approach to causality identify articles that focused on the key topics of describ- assessment on an individual level is warranted in cases of ing or evaluating methods for DILI causality assessment. suspected DILI. Forty-three manuscripts were selected for further review by The goal of this IQ DILI manuscript is to provide a the CWG, which determined whether they were relevant to review of existing industry best practices and recommen- the goals of this review and, therefore, retained for further dations for causality assessment in the setting of potential review. Thirty-two articles were recommended for addi- DILI. In collaboration with academic and government sub- tional review. Individual working group members reviewed ject matter experts (SMEs) and the IQ DILI Causality Work- assigned articles in depth and provided high-level written ing Group (CWG), this paper was developed to address the summaries to the team. following key objectives: Causality Assessment in DILI 2.2 Survey The survey was completed by 13 respondents (77% of which identifed themselves as large-size companies [> A blinded survey was developed by the CWG with the spe- 10,000 employees]) of which 70% had fve or more new drug cifc intent to collect information not available through a applications (NDAs) yearly. One company provided separate review of the scientifc literature and regulatory guidance. responses for two divisions of the organization. Sixty-nine The IQ CWG created