19 March 2014 DILI Conferences 1

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1 John R. Senior, M.D. Associate Director for Science Office of Pharmacovigilance and Epidemiology Office of Surveillance and Epidemiology Center for Drug Evaluation and Research Food and Drug Administration 19 March 2014 DILI Conferences 1

2 The DILI Conferences John R. Senior, M.D. Associate Director for Science Office of Pharmacovigilance and Epidemiology Office of Surveillance and Epidemiology Center for Drug Evaluation and Research Food and Drug Administration 19 March 2014 DILI Conferences 2

3 Why were they started? 1) troglitazone (REZULIN ) 2) bromfenac (DURACT ) Remarks made and opinions expressed do not reflect official positions or policies of the Food and Drug Administration, but are those of the author. 19 March 2014 DILI Conferences 3

4 Table 1. Safety Withdrawals for New Molecular Entities Approved by FDA in 1997 new drug date approved date withdrawn reason for withdrawal troglitazone REZULIN, P-D/W-L mibefradil, POSICOR,Roche cerivastatin, BAYCOL,Bayer bromfenac, DURACT,Wyeth sibutramine, MERIDIA,Abbott trovafloxacin, TROVAN, Pfizer alatrofloxacin, TROVAN IV, Pfizer 29 Jan Mar 2000 liver toxicity 20 Jun Jun 1998 fatal arrhythmias 26 Jun Aug 2001 rhabdomyolysis, renal failure 15 Jul Jun 1998 severe hepatitis, liver failure 22 Nov Oct 2010 risk of heart attack, stroke 18 Dec Jun 2006 liver toxicity 18 Dec Jun 2006 liver toxicity 19 March 2014 DILI Conferences 4

5 - We started thinking about a conference for FDA reviewers in July 1998, to see if we could understand it better, educate both reviewers and ourselves, maybe prevent trouble. - the first person asked to participate and help plan it was Hy Zimmerman --- he accepted, agreed to speak. We decided to call it Drugs and the Liver; What They Do to Each Other because - most drugs are metabolized by the liver; - but some drugs may cause injury to the liver. 19 March 2014 DILI Conferences 5

6 Hy Zimmerman March 2014 DILI Conferences 6

7 Hy said (Kober Lecture 1968), and wrote repeatedly (1978 and 1999 texts) that drug-induced hepatocellular jaundice is a serious lesion, with mortality of from 10 to 50 per cent Bob Temple was much impressed by this in 1978, observed it to be true at FDA for >20 years, and then dubbed it Hy s Law at the 1999 conference 19 March 2014 DILI Conferences 7

8 Center for Drug Evaluation and Research (CDER) Office of Training and Communication, Division of Training and Development; Committee for Advanced Science Education CDER STAFF COLLEGE COURSE ASE 0202 Drugs and the Liver: What They Do To Each Other University of Maryland, Shady Grove Campus Auditorium, Gaithersburg Monday, 19 April :00 Check-in, coffee 8:30 Welcome, Course Overview 8:35 The Problem of Drug-Induced Hepatotoxicity 8:45 Specific Examples (8-10 minutes each) bromfenac (DURACT) tasosartan (VERDIA) tolcapone (TASMAR) zileuton (ZYFLO) troglitazone (REZULIN) tacrine (COGNEX) 9:45 FDA Perspective on Drug-Hepatotoxicity John Senior, HFD-180 Bob Fenichel, HFD- 110 Mac Lumpkin, HFD-002 Ray Anthracite, HFD-570 Sol Sobel, HFD-5 10 Judy Racoosin, HFD-120 Randy Levin, HFD-120 Bob Temple, HFD :15 Break 10:45 Drug metabolism and hepatotoxicity in animals; Sharon Center, Cornell University choice of animal species for testing liver effects School of Veterinary Medicine 11:45 Pharmacology/toxicology preclinical assessments Andrea Weir, HFD :15 Lunch 1:15 Liver function and injury: what the tests mean John Senior, HFD-I 80 1:45 What we can learn from hepatic studies in vitro Jerry Collins, HFD-902 2:15 Human hepatotoxicity of drugs; toxicity or Jim Lewis, Georgetown University, speaking for Idiosyncracy, cellular or cholestatic? Hy Zimmerman, Armed Forces Institute of Pathology, 3: 15 Break 3:45 Detection of hepatoxicity during NDA review Tom Laughren, HFD :15 Clinical panel discussion: Lumpkin, Temple, Senior, Lewis, Zimmerman, Lee, Laughren 19 March 2014 DILI Conferences 8

9 Tuesday, 20 April :00 Coffee 8:30 Fialuridine and chronic hepatitis B David Feigal, HFM- I 8:45 Evaluating drug toxicity in patients with preexisting liver disease Will Lee, University of Texas, SW 9:45 Panel--special problems in treating hepatitis; Zimmerman, Lee, Lewis, Feigal, Senior,Graham, Lumpkin, Temple 10:30 Break 11:00 Post-marketing detection of hepatoxicity David Graham, HFD :30 Lessons learned and solutions to be found Mac Lumpkin, HFD :00 Lunch 1:00 Workshop description, questions for breakout groups Robert Temple; moderator...with respect to drug-induced hepatotoxicity, - what can be done better to: - detect it in animals and predict it in people? - use in vitro systems to predict it? - design clinical studies to detect it? - detect it during NDA review? - detect and characterize it post-approval? 1:15 Breakout sessions to discuss questions All Participants 2:45 Reports of breakout groups Breakout Group Spokespersons 3:30 General discussion in plenary session Faculty and Audience Consensus & Suggestions: What Might be Done Better 4:00 Adjourn {Attendance 325 FDA reviewers} [Program repeated for 75 more reviewers, November 1999, by R. Temple and J. Senior] 19 March 2014 DILI Conferences 9

10 NIH then put on a conference October 2000 on Drug-Induced Liver Injury: Mechanisms and Test Methods We followed February 2001 at Chantilly VA, including speakers from the pharmaceutical industry and academia, with Drug-Induced Liver Injury: A National and Global Problem No meeting in January 2002 because of the attacks of 9/11/2001) 21 January 2003, at The Rockville Mansion 5 February 2004, at The Rockville Mansion 28 January 2005, at The Rockville Mansion January 2006 at the Strathmore Music Center January 2007 at Brookfield Gardens March 2008 at the National Labor College 8-9 April 2009 at the National Labor College March 2010 at the National Labor College March 2011 at the National Labor College March 2012 at the National Labor College March 2013 at U MD Conference Center here were are again at the University of Maryland in March 2014 DILI Conferences 10

11 we developed edish, to help medical reviewers edish evaluation of Drug-Induced Serious Hepatotoxicity hyperbilirubinemia Hy's Law range Drug X Peak TBL, xulrr x Drug C 0.1 normal range 3x Temple's Corollary range Peak ALT, xulrr with Ted Guo, at CDER, March 2014 DILI Conferences 11

12 and now, in 2014, we are developing edish 2; - since 1998 FDA has not approved any drug that had to be taken off the market for liver toxicity! - FDA refused to approve ximelagatran in 2004, and lumiricoxib in 2007, despite their approvals in Europe; both were later found to be hepatotoxic in individuals with HLA DRB1*0701 or HLA DRB1*1501 susceptibility markers; --- the new driving force 2014: treatment and possible cure of chronic hepatitis C --- we don t want to miss a cure We at the FDA Center for Drug Evaluation and Research are in this together with The Critical Path Institute, the American Association for Study of Liver Diseases, and Pharmaceutical Research and Manufacturers of America. 19 March 2014 DILI Conferences 12

13 This year, 2014, we focus on review of what is being done at FDA/CDER by its major superoffices (new drugs, surveillance/epidemiology, and translational science), by the CPI, AASLD, as well as by CDER and PhRMA TO IMPROVE DETECTION OF SUSCEPTIBLE PATIENTS, MAKE CORRECT DIAGNOSES OF CAUSE, AND PREVENT SERIOUS DILI BEFORE IT S TOO LATE.... with major emphasis on progress in finding new and effective biomarkers. 19 March 2014 DILI Conferences 13