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

1. Study of Drug-Induced ALF in a Liver Transplant Network Study Design Issues Mark Avigan, MD CM Director, Division of Drug Risk Evaluation Office of Drug Safety CDER, FDA

3. 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

4. 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

5. 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.

6. 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

7. 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

8. 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

9. 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

10. 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?

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