Sequential steps in causality assessment are outlined in Fig. 1 . Complete clinical data, including serial laboratory test results together with the local ULN values, were extracted from the clinical records and entered into a 65-page case report form (CRF). To exclude conditions that can mimic drug-induced liver disease, the patients and their medical records were screened for previous liver disease, alcohol use, serological and virological evidence of hepatitis A, B, or C infection, autoantibodies, ceruloplasmin, alpha-1-antitrypsin, ferritin, and iron; additionally, results of imaging studies were reviewed. Patients who had not been fully evaluated when they were first identified underwent testing for any missing laboratory data at enrollment. Liver biopsy was not required for adjudication purposes, but if it was performed as part of routine clinical care, the results were collected and made available to reviewers. To facilitate adjudication, the extensive database was summarized in an abbreviated CRF that included such key elements as the date of onset of liver injury, complete information about all medications taken within 6 months of onset of the event, the presence of symptoms and signs of liver disease, pertinent past medical history, complete laboratory tests, imaging and liver biopsy results, and serial results for ALT, AST, AP, serum bilirubin, and the prothrombin time or INR.
In addition to the short CRF summary, a succinct case summary called the clinical narrative was completed by the study investigator who enrolled the subject. The narrative provided detailed information on the history and chronology of the illness with dates of drug initiation and liver disease onset, pertinent features of the liver disease, and the time to improvement or recovery. The narrative also included information on past use of the implicated agent and significant concomitant drugs, the past medical history, the extent of alcohol use, whether there had been an episode of hypotension, and information on the course of the illness, including hospitalization, a history of hepatic decompensation or organ failure, and death or liver transplantation. Finally, the investigator provided a rationale for ascribing the event to a specific medication or medications without offering a personal view on the estimated strength of the association.
In addition to the short CRF summary, a succinct case summary called the clinical narrative was completed by the study investigator who enrolled the subject. The narrative provided detailed information on the history and chronology of the illness with dates of drug initiation and liver disease onset, pertinent features of the liver disease, and the time to improvement or recovery. The narrative also included information on past use of the implicated agent and significant concomitant drugs, the past medical history, the extent of alcohol use, whether there had been an episode of hypotension, and information on the course of the illness, including hospitalization, a history of hepatic decompensation or organ failure, and death or liver transplantation. Finally, the investigator provided a rationale for ascribing the event to a specific medication or medications without offering a personal view on the estimated strength of the association.
