Drug Induced Liver Injury: A common challenge for the Drug Induced Liver Injury Network and Industry
Jose Serrano M.D, Ph.D. Livers Disease Research Branch Division of Digestive Diseases and Nutrition,
National Institute of Diabetes and Digestive and Kidney Diseases
Adverse Drug Reactions (ADR) are a significant clinical problem:
6.7% Inpatients have significant ADRs. 0.3% Fatal (106,000 deaths) 5th commonest cause of death in hospital
JAMA. 1998;279:1200-1205.
Leading cause for acute liver failure in patients referred for
liver transplantation.
Semin Liver Dis 2003,23, 217–26.
Hepatotoxicity is the most common single ADR leading to drug withdrawal and refusal for FDA approval JAMA 2002; 287, 2273–5.
DILI, a scientific opportunity
The increasing Public Health importance of ADRs The recognition of genetic variability as a determinant of the ADRs
The development of high throughput gene profiling and expression tools (genome-wide SNPs screening, expression arrays, proteomics, metabolomics) Advances in bioinformatics and computing,
Difficulties in detecting DILI in controlled clinical studies :
1.- Idiosyncratic DILI is rare (10-3 to 10-4).Unlikely to be
detected in typical clinical trials (102 to 103 persons)
.
2.- Extensive exclusion criteria limits the population exposed to the drug. 3.- Dosage and duration of treatment may not reflect drug usage in clinical practice.
Difficulties of detecting DILI in clinical practice:
1.- There are no clinical features that are diagnostic of DILI (Diagnosis of exclusion). 2.- Diagnosis requires accurate and exhaustive contemporaneous collection of data.
(time- and resource-consuming).
3.- Diagnosis requires a high level of clinical suspicion and expertise (Surveillance attitude).
Difficulties of detecting DILI in clinical practice:
4.- Reporting adverse events to the FDA (AERS database) is voluntary.
5.- AERS receives over 1000 reports daily from physicians, nurses, pharmacist, patients and relatives
(variable levels of training in clinical pharmacology and supportive evidence).
6.- AERS data are often incomplete and inadequate, being collected from different sources without expertise or standardization of terms and diagnostic criteria. Toxicologic Pathology, 33:155–164, 2005
Needed to fully define the incidence, pathogenesis and clinical features of DILI:
1.- Initiate prospective testing for liver injury of all patients exposed to each new drug (i.e clozapine) 2.- Develop a better means of capturing a sizeable and representative sample of cases of DILI: the focus of the Drug Induced Liver Injury Network (DILIN)
Drug Induced Liver Injury Network
DILIN
A Cooperative Agreement funded by the Division of Digestive Diseases and Nutrition,
National Institute of Diabetes and Digestive and Kidney Diseases
Drug Induced Liver Injury Network DILIN Cooperative Agreement
NIDDK:
Jose Serrano MD; PhD (Project Scientist). Jay Hoofnagle, MD, Leonard Seeff MD, Jay Everhart, MD, M.P.H. (Scientific Advisors)
Data Coordinating Center
James Rochon PhD Duke University
Five Clinical Research Centers
DILIN Clinical Centers
University of Connecticut. Herbert Bonkovsky MD
NE Consortium 12 academic, 5 community, 3 pediatric, 1 VA
Indiana University. Naga Chalasani MD
1 academic (adult and pediatric), 1 VA, 5 community, CAM pain center, state poison center
University of Michigan. Robert Fontana MD
1 academic, 1 VA, 4 community
DILIN Clinical Centers
University of North Carolina. Paul Watkins MD
3 academic, 4 community, 2 pediatric, 1 VA
University of California San Francisco. Tim Davern MD
3 academic centers, 2 community, Script II TB network, SFGH, 1 pediatric, 1 large HMO, CAM Trial
DILIN: Sphere of Influence
12.8 million persons
Drug Induced Liver Injury Network: Ongoing Studies 1). Limited retrospective study
Idiosyncratic Liver Injury Associated with Drugs (ILIAD)
2). Prospective study Drug Induced Liver Injury Network (DILIN) study
DILIN: Objectives
Develop standardized instruments to identify and fully characterize bona fide cases of drug, CAM and toxin- induced liver injury.
Analyze of the epidemiology and clinical spectrum of hepatotoxicity.
Obtain biological samples for study of the pathogenesis of hepatotoxicity using biochemical, serological and genetic techniques .
DILIN: Goals
Elucidate the genetics and the mechanisms of hepatotoxicity. Provide the foundation for the development of molecular screening tools to prevent druginduced liver toxicities.
Understanding the pathogenesis and clinical features of hepatotoxicity and serve as a regional and national clinical resource.
Can the pharmaceutical industry benefit from participation in the DILIN? Yes!
Disclosure: the opinions expressed are my own and do not represent the official position of the NIDDK
DILIN: benefits for industry participation
Intellectual satisfaction to contribute to the solution of a difficult and important public health problem. Access to an independent panel of experts. Access to biosamples to study mechanisms.
DILIN: benefits for industry participation
Public relation/trust and corporate image/brand improvement. Understanding DILI will lead to “personalized prescription practices” keeping drugs in the market for those not at risk. Participation in DILIN could impact the regulatory position of the FDA.
Industry contribution to DILIN
Referring patients from the preclinical, clinical and post marketing phases. Contribute funds to expand the network to more centers. Contribute expertise. Support ancillary studies on mechanisms of injury.
How can a partnership between Industry and DILIN be built? Are there obstacles to that partnership?
Jose Serrano M.D., Ph.D. Liver Disease Research Branch Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases 2 Democracy Plaza, Room 657, MSC 5450 BETHESDA MD 20892-5450
Phone 301 594-8871 FAX EMAIL: js362q@.nih.gov 301 480-8300
For Courier service use: 6707 Democracy Blvd, Room 657 BETHESDA MD 20817