[Show abstract][Hide abstract] ABSTRACT: Background/Aims Drug Induced Liver Injury (DILI) is a major cause of liver failure in the US and the leading reason for failure of investigational drugs in clinical trials, lack of drug approval, and post-market withdrawal of approved drugs. Recent genome-wide association studies have identified variations within the major histocompatibility complex in Caucasians to be linked with flucloxacillin and lumiracoxib-related liver injury. The need for replication of these findings and extension of these investigations to other drug exposures and other ethnic groups will require substantial case numbers with supporting medical record documentation. With support from The Serious Adverse Event Consortium, an international consortium led by the pharmaceutical industry in conjunction with the FDA, we conducted a feasibility study to evaluate the potential for using electronic clinical and administrative data from two HMORN sites to identify provisional DILI cases. Methods Building upon previous research, we developed data specifications for electronic searches of ICD-9 codes with time proximate laboratory results indicative of liver-related disease. Electronic criteria were used to 'rule out' other liver diseases and other co-morbid conditions indicative of systematic liver-related effects. For feasibility testing, two methods of population identification were incorporated: the VDW and EMR reporting. All records from 1/1/00-8/1/09 that were identified as 'potential DILI cases' were reviewed manually, and selected data were abstracted, including suspected implicated drug(s). Results Records for 1,123,173 individuals were screened for potential case status; 29,893 records with one or more diagnoses of interest were identified. After application of the "rule out' exclusion criteria, 584 potential DILI cases were reviewed and 99 ultimately met provisional case status. Drugs commonly associated with provisional DILI cases were sulfa-containing antibiotics, anticonvulsants, isoniazid, and statins. Roughly one-half of provisional DILI cases were associated with a single implicated drug. Conclusions Electronic infrastructures currently available within many highly integrated health care delivery systems can be efficiently leveraged to support identification of provisional DILI events. Systems that have comprehensive episodic, historic and post-event data, including lab, diagnostic, treatment, imaging, and medication records that can be accessed electronically should be considered primary systems for expanding DILI case accumulation efforts.
Clinical Medicine & Research 11/2011; 9(3-4):180. DOI:10.3121/cmr.2011.1020.ps1-31
[Show abstract][Hide abstract] ABSTRACT: Background/Aims The International Serious Adverse Events Consortium (iSAEC) is a pharmaceutical industry and FDA-led consortium focused on identifying DNA variants useful for predicting risk of drug-induced rare serious adverse events (SAEs). We assessed the feasibility of using electronic medical databases at six HMORN sites to identify provisional cases of three SAEs: drug-induced liver injury (DILI), serious skin rashes (SSR), including Stevens-Johnson syndrome, toxic epidermal necrolysis, and angioedema, and extreme weight gain (EWG) among adults on atypical antipsychotics. Methods Project work was divided among three teams. HealthPartners and Marshfield Clinic led the DILI team, Kaiser Permanente Hawaii and Kaiser Permanente Georgia led the SSR team and Group Health and Geisinger guided the EWG study. Teams met routinely via biweekly conference calls to coordinate their study efforts; monthly conference calls were conducted to coordinate the overall project, mark progress and discuss challenges and solutions. For each study, standardized case identification criteria were developed with input from iSAEC, expert panels, and medical literature. Potential cases were identified through electronic data searches using diagnoses, medication histories, laboratory test results, and other clinical data elements indicative of DILI and SSR during 2000-2009, or EWG from 2004-2009. Potential cases of DILI and SSR were abstracted to assess provisional case status and determine implicated drugs. Weight trajectories of suspected EWG cases were visually inspected to confirm EWG during atypical antipsychotic treatment period. Results A total of 99 provisional cases of DILI, 41 cases of SJS/TEN and 56 provisional cases of angioedema were identified from the electronic records of the participating HMOs. For EWG, 249 cases were confirmed and an additional 341 were categorized as "possible" cases, with additional chart review and patient interview required for confirmation. Confirmation rates varied from 17% for DILI to 2-79% for SSR and 23-30% for EWG. Conclusions The SAEC and HMORN study sites identified well-phenotyped cases with the targeted drug-induced SAEs of interest. The relative success of these efforts has been critical in the planning of a larger second study that will include analyses of genetic factors associated with provisional case SAEs.
Clinical Medicine & Research 11/2011; 9(3-4):180-181. DOI:10.3121/cmr.2011.1020.ps1-18