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Recognizing Drug-Induced Liver Injury (DILI) in Exposed Populations

Recognizing Drug-Induced Liver Injury (DILI) in Exposed Populations

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Recognizing Drug-Induced Liver Injury (DILI) in Exposed Populations

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  1. Recognizing Drug-Induced Liver Injury (DILI) in Exposed Populations John R. Senior, M.D. Associate Director for Science Office of Pharmacoepidemiology and Statistical Science Food and Drug Administration (FDA) FDA/CDER-AASLD-PhRMA HepTox Steering Group

  2. Material presented here is based on the observations of the speaker for 20 years in academic hepatology and gastroenterology, 5 years as a senior executive in the pharmaceutical industry, 11 years in private consulting to industry, and upon 9.5 years at the FDA: 4.5 years as a medical reviewer for new gastrointestinal drugs, 3 as the Senior Scientific Advisor for hepatology in the Office of Drug Safety, 2 years as Associate Director for Science, Office of Pharmacoepidemiology and Statistical Science. Comments made here do not reflect official policies or positions of the Agency, but are personal opinions of the presenter based on his diverse experiences mentioned. FDA/CDER-AASLD-PhRMA HepTox Steering Group

  3. First, Detect it ! (if you don’t ask or look, you won’t get or find) Ask: Is there liver injury or disease? serum transaminases, other enzymes, bilirubin, INR Is it progressive or serious? progressive = getting worse or likely to do so serious = disabling, life-threatening, fatal Drug-induced or some other cause? no pathognomonic test for DILI, including biopsy DILI may mimic any known liver disease FDA/CDER-AASLD-PhRMA HepTox Steering Group

  4. “some other causes” What are they? mainly acute hepatitis : viral A or B, seldom C, alcoholic, biliary stones, ischemic, or autoimmune; other causes rarer How can they be ruled out? what information should be collected? What are the odds of other causes? It’s really a problem of differential diagnosis. FDA/CDER-AASLD-PhRMA HepTox Steering Group

  5. Drug-Induced Liver Injury (DILI) Most people exposed to a new drug show no injury; “tolerators” Some people show transient injury, but adapt; “adaptors” A few fail to adapt and show serious toxicity ! “susceptibles” FDA/CDER-AASLD-PhRMA HepTox Steering Group

  6. Drug-Induced Liver Injury (DILI) “tolerators” FDA/CDER-AASLD-PhRMA HepTox Steering Group

  7. Drug-Induced Liver Injury (DILI) “adaptors” FDA/CDER-AASLD-PhRMA HepTox Steering Group

  8. Drug-Induced Liver Injury (DILI) “susceptibles” FDA/CDER-AASLD-PhRMA HepTox Steering Group

  9. … not DILI FDA/CDER-AASLD-PhRMA HepTox Steering Group

  10. Is It a Bad Drug or Is It aSusceptible Patient? Why do a few people not tolerate it? What’s different about them? Can we find out? A drug tolerated by nearly everybody except a very few cannot be considered “toxic.” And not give them this drug? FDA/CDER-AASLD-PhRMA HepTox Steering Group

  11. Given: Some Drugs are More Toxic • many or most eliminated in development • molecular variations in class • differing potencies of variants • therapeutic index varies • variable PK ADME among patients • variable PD responses in patients • one dose may (will) not suit all patients FDA/CDER-AASLD-PhRMA HepTox Steering Group

  12. Relative Hepatotoxicity in Class“- glitazones” (thiazolidenediones)peroxisome proliferator-activatedreceptor- (PPAR) agents FDA/CDER-AASLD-PhRMA HepTox Steering Group

  13. FDA/CDER-AASLD-PhRMA HepTox Steering Group

  14. The Glitazone Family FDA/CDER-AASLD-PhRMA HepTox Steering Group

  15. “-profens” benoxaprofen flurbiprofen ibuprofen “-fenacs” ibufenac bromfenac diclofenac “-pidems” alpidem zolpidem “-navirs” ritonavir indinavir nefinavir saquinavir Other Drug “Families” FDA/CDER-AASLD-PhRMA HepTox Steering Group

  16. Need research on . . . 1) which cytochrome isoforms attack what part of the molecules? 2) which metabolites are more toxic? 3) proof that efficacy and toxicity are in different parts of same molecule ? 4) some rules to predict DILI 5) mechanisms causing the DILI 6) not just in animals, but in humans FDA/CDER-AASLD-PhRMA HepTox Steering Group

  17. Should We Be Looking More Carefully at the Patients ? Humans are often very different than animal models They are incredibly diverse genetically They resist being standardized or controlled They take a lot of drugs, diets, supplements, alcohol They have lots of other diseases/disorders/activities The ones treated are not the same as the ones studied They don’t always report troubles promptly FDA/CDER-AASLD-PhRMA HepTox Steering Group

  18. "Our study is man, as the subject of accidents or diseases. Were he always, inside and outside, cast in the same mould, instead of differing from his fellow man as much in constitution and in his reaction to stimulus as in feature, we should ere this have reached some settled principles in our art. The practice of medicine is an art, based on science ... it has not reached, perhaps never will, the dignity of a complete science, with exact laws, like astronomy or engineering.” William Osler, M.D. (1849-1919) “Teacher and Student,”Minneapolis 1892 FDA/CDER-AASLD-PhRMA HepTox Steering Group

  19. "…he who aspires to treat correctly of human regimen must first acquire knowledge and discernment of the nature of man in general – knowledge of its primary constituents and discernment of the components by which it is controlled. … though they are made from the same materials, no two are alike…” Hippocrates 460-377 B.C. The Father of Medicine FDA/CDER-AASLD-PhRMA HepTox Steering Group

  20. Hippocrates “Nature of Man” elements qualities constituents fire hot blood water wet phlegm air cold bile - yellow earth dry bile - black “Airs, Waters, Places” “Epidemics” “Nutriment” FDA/CDER-AASLD-PhRMA HepTox Steering Group

  21. Why Are They Susceptible ? “idio-sug-krasia” (Hippocrates, ~ 400 B.C.) idios () - one’s own, self syn () - together crasis () - mixing, mixture therefore, a person’s own individual mixture of characteristics, factors; “nature and nurture,” unique in the world [it does NOT mean rare, unexpected, unexplained, although it may or may not be any or all of them] FDA/CDER-AASLD-PhRMA HepTox Steering Group

  22. 4*4@FL(6DVF4V (idiosugkrasia) s.f., (substantive, feminine) temperament; constitution Pocket Oxford Greek Dictionary Oxford University Press, Oxford UK, 2000 FDA/CDER-AASLD-PhRMA HepTox Steering Group

  23. Factors in Idiosyncrasy genetic, bestowed at conception gender cytochromes, enzymes, transport systems acquired in life since conception age, activities, travels infections, immunities, diseases diet, obesity, dietary supplements other drugs, chemical exposures FDA/CDER-AASLD-PhRMA HepTox Steering Group

  24. Especially Susceptible Patients • adverse effect, often not dose-related • may not be duration-related • may not depend on prior disease • unexpected, unpredictable (up to now) • risk factors not well known • toxicity often uncommon or rare • who are they? how can they be identified? FDA/CDER-AASLD-PhRMA HepTox Steering Group

  25. Drug Development Issues: Idiosyncratic Drug Toxicity Occurs despite careful preclinical testing in animals … and despite careful and costly clinical trials Some problem (perhaps wrong) assumptions: Assuming drug variability is the key to safety Obsolete concepts of “safe and effective” – for all? Assuming one dose/regimen suits all patients Focus on efficacy, little on safety (especially if rare) FDA/CDER-AASLD-PhRMA HepTox Steering Group

  26. Needles in the HaystackTyranny of the Numbers - I if only 1 patient in 1000 reacts adversely to a drug, should we call the drug “toxic”? If 1 person in 1000 is idiosyncratically hyper-susceptible to show drug-induced liver injury, how many patients need to be observed to have 95% chance of finding at least 1? FDA/CDER-AASLD-PhRMA HepTox Steering Group

  27. A Binomial Answer . . . - if i = incidence of a rare event, and u = usual absence of the event, then (i + u) = 1, it happens or it doesn’t. And (i + u)N, where N = number of persons - when uN, the chance of seeing no events in a group of N persons, is <0.05, then the chance of seeing at least one is >95%, because 1 – uN = 1- <0.05 = >95% - for (0.001 + 0.999)N, need 2995 people to make (0.999)2995 = 0.04996, which is <0.05; - in general, N  3/i for rare events. FDA/CDER-AASLD-PhRMA HepTox Steering Group

  28. Detection of Rare Safety Problems • Before approval and marketing • NDA review: seldom have enough patients, so rare but serious event may not be observed; but if they are seen, investigate! • After marketing and clinical use • spontaneous, voluntary reporting useful, but severely underreported and incomplete data • problems usually worse after marketing FDA/CDER-AASLD-PhRMA HepTox Steering Group

  29. Liver “Function” Tests • what are they ? • what do they mean ? Important: distinguish between liver function and liver injury • they’re the biomarkers we use FDA/CDER-AASLD-PhRMA HepTox Steering Group

  30. Commonly Used Tests injury “transaminases”: ALT AST hepatocellular cholestatic enzymes alkaline phosphatase gamma-glutamyl transferase function excretory synthetic synthetic bilirubin (total, “direct”) albumin prothrombin (INR) substances FDA/CDER-AASLD-PhRMA HepTox Steering Group

  31. Is Serum ALT a Liver Function Test ? • serum enzymes not just from liver but also from skeletal and heart muscle, gut, etc. • . . . so let’s not assume “liver” • it is not a function or job of the liver to regulate the level of serum enzyme activity • . . . so let’s not say “function” • elevated serum ALT activity MAY indicate hepatocellular injury FDA/CDER-AASLD-PhRMA HepTox Steering Group

  32. Is Serum Transaminase Enough? FDA/CDER-AASLD-PhRMA HepTox Steering Group

  33. Need Very, Very Specific TestsTyranny of the Numbers - II • For relatively low prevalence or incidence events, need extremely high specificity of test to avoid “finding” many false positives • Almost impossible to find a hyper-specific test; compound tests may help: ALT+TBL • Probably need to add clinical differential diagnostic data and methods to attain FDA/CDER-AASLD-PhRMA HepTox Steering Group

  34. Hy Zimmerman 1917-1999 FDA/CDER-AASLD-PhRMA HepTox Steering Group


  36. “intrinsic” predictable dose-related similar in animals high incidence short interval types directly destructive indirect, metabolic cholestatic “idiosyncratic” unpredictable not dose-related not seen in animals low incidence, rare variably longer interval types hypersensitivity metabolic …H. Zimmerman, 1978 Intrinsic vs Idiosyncratic Toxicity FDA/CDER-AASLD-PhRMA HepTox Steering Group

  37. Relative Importance for Hepatotoxicity phosphorus amanita phalloides carbon tetrachloride anabolic steroids tetracycline chlorpromazine phenytoin penicillin Intrinsic Toxicity ------------------------------------some of both--------------------------------------- Host Susceptibility ___________________________________________________________________________________________ HZ…but that’s an oversimplification!“…this dichotomy into intrinsic toxicity or host idiosyncracy is an overly simplified formulation. The potential for injury is arranged along a spectrum, … modified by several different mechanisms.” FDA/CDER-AASLD-PhRMA HepTox Steering Group

  38. “Hy’s Law” ...for drug-induced hepatotoxicity • If both hepatocellular injury and jaundice occur, look out for at least 10% mortality! • i.e., when both transaminase and bilirubin elevations occur together. Robert Temple, FDA, 1999 FDA/CDER-AASLD-PhRMA HepTox Steering Group

  39. Searching for Clues, Predictors • Can ways be found to search pre-approval clinical databases (NDA submissions) for clues or “signals” that predict liver failure in at least some who show the signal? • Hy Zimmerman was on to a key concept - the combination of an indicator of injury and loss of overall function may be a valid predictor. It needs confirmation. FDA/CDER-AASLD-PhRMA HepTox Steering Group

  40. “Temple’s Corollary” ...for drug-induced hepatotoxicity:Hy’s Law cases arise out of a background of increased incidence of transaminase elevations • Hy’s Rule-type serious cases of DILI usually arise from a background of increased injury rates, so • Look for more ALT elevations in those exposed to drug, compared to placebo or control drug. Robert Temple, FDA, 2004 FDA/CDER-AASLD-PhRMA HepTox Steering Group

  41. FDA/CDER-AASLD-PhRMA HepTox Steering Group

  42. What to Do When a “Signal” Detected • “signal” = laboratory abnormality, complaint, finding • immediately (within day or two) confirm by repeat tests, examination, questions • investigate possible causes AT ONCE ! r/o disease • start close observation (3x/week) immediately • obtain more information about possible causes • obtain consultation as appropriate or needed • follow closely (weekly, prn) to normalization or worsening and management decision FDA/CDER-AASLD-PhRMA HepTox Steering Group

  43. It may be DILI if it’s nothing else • Diagnosis of exclusion; no test FOR DILI • Must gather data to rule out other causes • Need to educate “docs” to do it better • Develop model for quantitative likelihood estimate • Prospective large safety studies needed: • for true incidence • for risk factors and to design risk management plans • for ‘omic’ analyses (gen-, prote-, metabon-) specimens • for elucidation of mechanisms FDA/CDER-AASLD-PhRMA HepTox Steering Group

  44. Tip of the Iceberg Death or Tx Acute Liver Failure Serious DILI – Threatening Detectable DILI – but Not Serious Patient Adaptation to New Agent Exposure Patients/People Tolerate Exposure Without Effects FDA/CDER-AASLD-PhRMA HepTox Steering Group

  45. Serious Adverse Events • Often have relatively low incidence rate, i • Difficult to establish correct value for i • Voluntary reporting gives uncertain values • May be missed in the usual efficacy trials • Must balance modest clinical benefits for many against serious risks for a few • Spontaneous reports (AERS) not enough FDA/CDER-AASLD-PhRMA HepTox Steering Group

  46. Retrospective Database Studies • Epidemiologic, observational – closer to reality • A definite improvement on spontaneous reports • Limited to who was included, data recorded • No attribution of causality; statistical differences • Can improve estimates of incidence, risk factors • But cannot investigate mechanisms or causes or “do it right” in real time, collect specimens FDA/CDER-AASLD-PhRMA HepTox Steering Group

  47. How many patients to study? • Prospective, not retrospective • Focus on safety, as drug actually prescribed • Large and long enough to find rare events • Full accounting, numbers of cases/exposed • Use patient self-reporting, then investigate possible cases intensely; get needed info • Prospective case-control design • Impartial study conduct: NIH or AHRQ FDA/CDER-AASLD-PhRMA HepTox Steering Group

  48. Prospective Large Safety Studies • Offer best chance to learn, and to protect patients • Need to establish true incidence of DILI • Need to identify risk factors for rational RM • Need to investigate mechanisms • In best interests of everybody, including patients, regulators, and sponsors • In 2005, are we content with safety meaning “not poison,” and withdrawing “toxic” drugs ? FDA/CDER-AASLD-PhRMA HepTox Steering Group