# Presentation: 755723

## Drug Induced Liver Injury: 

- Livers Disease Research Branch
- Division of Digestive Diseases and Nutrition,
- National Institute of Diabetes and Digestive and Kidney Diseases

- Drug Induced Liver Injury:
- A common challenge for the Drug Induced Liver Injury Network and Industry

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Leading cause for acute liver failure in patients referred for liver transplantation. 		Semin Liver Dis 2003,23, 217–26.

**6.7% Inpatients have significant ADRs. **
**0.3% Fatal (106,000 deaths)**
**5****th**** 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.*

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## DILI, a scientific opportunity

- 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,

**DILI, a scientific ****opportunity**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## 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 (10****2**** to 10****3 ****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.

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Difficulties of  detecting DILI 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).**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## 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**

- Difficulties of  detecting DILI in clinical practice:

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 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)**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## 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**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## Drug Induced Liver Injury  Network DILIN     Cooperative Agreement

**Data Coordinating Center**
**James Rochon PhD  **
**Duke University**

**NIDDK:**
**Jose Serrano MD; PhD (Project Scientist). **
**Jay Hoofnagle, MD, Leonard Seeff MD, Jay Everhart, MD, M.P.H.**
**(Scientific Advisors)**

**Five Clinical ****Research**** Centers**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## University of  Connecticut. Herbert Bonkovsky MD 

**University of  Michigan.   Robert Fontana MD**
**1 academic, 1 VA, 4 community**

**Indiana University.  Naga Chalasani MD**
**1 academic (adult and pediatric), 1 VA, **
**5 community, CAM pain center, state poison center**

**University of  Connecticut. Herbert Bonkovsky MD**
**NE Consortium  12 academic,  5 community,  3 pediatric, 1 VA**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## 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 Clinical Centers**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## DILIN: Sphere of Influence

**DILIN: Sphere of Influence**

**12.8 million persons**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

** **
** **
** **

**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**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## DILIN: Objectives

** ****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: Objectives**

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## DILIN: Goals

** ****Provide the foundation for the  development of   molecular screening tools to prevent drug-induced liver toxicities.**

**DILIN: Goals**

** ****Understanding the  pathogenesis and clinical features of ** **hepatotoxicity  and serve as a regional and national clinical resource. **

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## 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***

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## DILIN: benefits for industry participation

**DILIN: benefits for industry participation**

- Access to biosamples to study mechanisms.

- Intellectual satisfaction to contribute to the solution of a difficult and important public health problem.

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## DILIN: benefits for industry participation

**DILIN: benefits for industry participation**

- Participation in DILIN could  impact the regulatory position of the FDA.

- Public relation/trust and corporate image/brand improvement.

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

##  Industry  contribution  to DILIN

- Contribute funds to expand the network to more centers.

- Contribute expertise.

- Referring patients from the preclinical, clinical and post marketing  phases.

- Support ancillary studies on mechanisms of injury.

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005

## 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    301 480-8300
- EMAIL: js362q@.nih.gov
**For Courier service use:**
- 6707 Democracy Blvd, Room 657  BETHESDA MD 20817

- FDA/CDER-AASLD-PhRMA HepTox Steering Group

- 28 January 2005