Causality Assessment for Suspected DILI During Clinical Phases of Drug Development

Abstract

Causality assessment is a critical step in establishing the diagnosis of drug induced liver injury (DILI) during drug development. DILI may resemble almost any type of liver disease, and often presents a serious challenge to clinical investigators and drug makers. The diagnosis of DILI is largely based upon a combination of a compatible clinical course, exclusion of all other reasonable causes, resemblance of clinical and pathological features to known features of liver injury due to the drug (i.e., “drug’s signature”), and incidence of liver injury among patients treated with the drug compared to placebo or comparator. Causality assessment for suspected DILI is currently performed using either evaluation by physicians with expertise in liver disorders (i.e., expert opinion) or standardized scoring instruments such as the Roussel Uclaf Causality Assessment Method (RUCAM). Both approaches are widely used in the post marketing setting. Causality assessment based on expert opinion is considered superior to standardized instruments such as RUCAM, in the setting of drug development, and is currently the preferred approach during clinical trials. There is a need for a systematic revision of RUCAM that will render it more suitable for the setting of clinical trials and drug development. Careful monitoring and meticulous data collection during clinical trials are essential in all cases with established liver injury to allow for a proper causality assessment. A workshop was convened to discuss best practices for the assessment of drug-induced liver injury (DILI) in clinical trials. This publication is based on the conclusions of this workshop.

The Art and Science of Diagnosing and Managing Drug-induced Liver Injury in 2015 and Beyond

“…Given the advances made in identifying and excluding other causes of acute liver disease in the past 25 years, RUCAM is overdue for a re-evaluation and revision (64) (supplemental Table 9) . Indeed, owing to its inherent pitfalls, RUCAM is not used as the sole causality assessment method in the DILI Network (150), nor by many other DILI experts (64,65). The DILIN approach is to incorporate expert opinion (or what Senior refers to as "medical reasoning" [151]) into the elements of RUCAM to arrive at a percentage likelihood that the drug under question is responsible (150) (supplemental Table 10).…”

“…In the clinical trial setting, it is easier to regulate the type and number of tests that are performed compared to the office or hospital setting where a high index of suspicion is required (64,65) In the clinical trial setting, sponsors who want to do everything possible to exonerate their drug under development may opt to obtain every test conceivable to exclude alternatives. In the office setting, however, clinicians often direct their evaluation on the basis of symptoms and the height of the liver tests along with the injury pattern, to decide what diagnostic tests would be best, although causality often seems directly proportional to the number of exclusionary tests conducted.…”

Cellular and Molecular Aspects of Drug-Induced Liver Toxicity: Recent Prominent Mechanisms

“…DILI can be predictable, dose-related or unpredictable, unrelated to the dose of the drug on question. DILI can exist as hepatocellular damage, cholestatic damage (usually less serious than hepatocellular), or mixed damage [50]. The risk factors associated with DILI include age (<18 or >65years), obesity, pregnancy, concomitant alcohol consumption, and certain genetic polymorphisms (such as cytochrome P450 polymorphisms).…”

“…The risk factors associated with DILI include age (<18 or >65years), obesity, pregnancy, concomitant alcohol consumption, and certain genetic polymorphisms (such as cytochrome P450 polymorphisms). It has been suggested that susceptible populations should not be subjective to re-challenge with drugs suspected of causing DILI [49,[50][51][52][53]. These injuries resemble almost all known liver diseases and there are no pathognomonic findings, even upon liver biopsy, that clarify the diagnosis of DILI.…”

Toxicidad hepática causada por medicamentos: revisión estucturada

“…Para establecer la probabilidad de que un fármaco esté asociado con hepatotoxicidad, se han desarrollado escalas clínicas, como la Roussel Uclaf Causalita Assessment Method (CIOMS/RUCAM) y la Clinical Diagnostic Scale o Maria-Victorino Scale (M&V CDS). Se considera que la escala CIOMS/RUCAM, por su validez de contenido y de criterio, es la más adecuada y genera resultados compatibles con el juicio médico y la opinión de expertos sobre hepatotoxicidad; sin embargo, debido a lo dispendioso de su aplicación, su utilidad en la práctica clínica es limitada (36)(37)(38).…”