Study of Drug-Induced ALF in a Liver Transplant Network Study

							Study of Drug-Induced ALF in a Liver Transplant Network
Study Design Issues
February 5, 2004

Mark Avigan, MD CM Director, Division of Drug Risk Evaluation Office of Drug Safety CDER, FDA

‘The Acute Liver Failure Active Survellance Program’ - Ancillary Study
 Proposed to CDER’s Regulatory Science and Review Enhancement Committee (RSR/CDER) for 3/2000-2001 funding  ODS Investigators - M. Willy, Ph D; J. Staffa; Ph D, RPh
 ODS Collaborators - D Graham, MD MPH; P Honig, MD, MPH; E. Rodriguez MD MPH
 External Collaborator – W. M. Lee, Clinical Center of Liver Disease, University of Texas, Southwestern Medical Center

 Status of Proposal – Not funded

Proposed study – Collaboration with the US Acute Liver Failure Multicenter Study Group (ALFSG) to improve detection of ALF and identify possible patient risk factors
 ALFSG Resource – Multi-center Liver Xplant Network coordinated by W. Lee
 Plans - sites distributed throughout US (up to 39 sites); ~ 5 - ? % volume of ALF patients in US
 Currently identifies approximately 100-200 ALF patients/yr; ~15 % drug-related, not linked to APAP  Support - NIH funded through 2005

ALFSG Aims
 Collection of clinical and epidemiologic data
surrounding drug-induced ALF  Serum and tissue repository  Registry of ALF patients  Randomized trial - N-acetylcysteine treatment of patients with non-acetaminophen ALF

Aims of collaborative study
 Validation of medication histories by review of
primary healthcare provider’s medical records (completeness and accuracy)  In-depth clinical reviews of all drug-related and ‘indeterminate’ cases.

Identification of:
 previously unrecognized hepatotoxins
 drug-drug effects of known hepatotoxins  new cases of known hepatotoxins  suspicious drugs in indeterminate cases  demographic characteristics  possible patient risk factors

Determination of:
 representativeness/completeness of ALF cases  comparability of proportion/characteristics of collected cases with non-referred cases  drug-induced ALF incidence (non-referred cases and those collected in Liver X-plant centers not part of ALFSG; obtained from UNOS)  common demographic/clinical/medication/biological characteristics of patients with ALF  hypotheses of susceptibility mechanisms/risk factors

Study Design Issues
 Appropriate resource to identify drugs/injury mechanisms associated with ALF  Drug-induced ALF is rare
 net must be large  drug usage (patient-yrs; mean duration/dosaging of Rx; exposure of susceptible patients, etc.) must be sufficient

 Percentage of all US patients must be high for ‘checkbox’ to r/o ALF cases associated with newly marketed drug  A smaller network may be useful as a ‘watchtower’ to identify/confirm cases of ALF if high exposure of drug in population

Study Design Issues contd.
• ALF pharm/tox mechanisms are heterogeneous
 organism/cell/molecular interactions  patient susceptibility factors  biochemical profiles and tempos of clinical presentation

• ‘Splitting’ of case materials collected in a ‘lumped’ resource likely necessary to study initiation of injury • ‘Lumping’ of case materials may be ok for study of common end-stage pathological processes • Number of patients who develop reversible (severe) DILI without ALF likely larger that those with ALF
 study linked to greater chance of ‘capture’ in health care networks

Questions for Discussion
• Numbers with non-APAP drug-induced ALF in ALFSG; percentage of US pool • Size/representiveness of ALF patients in ALFSG
 ‘checkbox’ for new drugs?  ‘watchtower’ for drugs with high exposure in the population?

 Biases in referrals to ALFSG
 under-representation of certain drug toxicities?

Questions for Discussion contd.
Practical barriers in clinical assessment, material collection and effective reporting  Linkage of basic/clinical science investigators with ALFSG  Basis to identify/study patients prospectively /retrospectively with DILI in referring health care system
 what barriers exist to identify/report patients?  how proposals are prioritized?
 what ancillary resources/IT tools are useful to develop?