215

DILI and Drug Development: A Regulatory Perspective Mark I. Avigan, MD, CM1

Administration, Silver Spring, Maryland Semin Liver Dis 2014;34:215–226.

Abstract

Keywords

► drug-induced liver injury ► hepatotoxicity ► biomarkers ► clinical trials ► postmarketing drugrisk evaluation

Address for correspondence Mark I. Avigan, MD, CM, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993 (e-mail: [email protected]).

The assessment of risk for serious, life-threatening drug-induced liver injury (DILI) associated with a suspect drug, biological agent, or herbal product depends on an iterative analysis of pre- and postmarket datastreams. Because serious cases of idiosyncratic DILI are typically rare, regulatory scientists seek strategies that accurately predict from clinical trial data which study drugs will be likely to cause these events in a large postmarket treatment population, e.g., through the identification of cases that are consistent with Hy’s law. This objective is only achievable if rigorous standards in study subject monitoring, data collection and analysis of liver injury cases for causality are followed. In the future, the development of more effective predictive and analytic tools in preclinical and clinical testing will provide a framework to reliably identify new agents that have hepatotoxic profiles as well as those individuals who are susceptible to develop serious DILI.

Historical View of DILI and the FDA Since passage of the Food, Drug and Cosmetics Act by Congress in 1938, the U.S. Food and Drug Administration (FDA) has had a central regulatory role in determining whether new drugs are both safe for human use and appropriately labeled.1 In 1962, after several drug-induced toxicities gained public attention, including a spate of serious birth defects caused by thalidomide, the federal agency’s mandate was broadened with a requirement for manufacturers of new agents to measure both efficacy and safety outcomes in clinical trials. These measures provided a framework for an analysis of overall benefits and risks in the drug approval process. Over subsequent years, a series of new laws and federal regulations have been instituted to further improve drug-related risk assessment and mitigation. It is notable that several important advances in regulatory decision making surrounding new therapeutic drugs have been influenced by lessons learned from therapeutic agents, which have turned out to cause serious hepatotoxicity in postmarket treatment populations. To date, over 50 drugs have been withdrawn from the United States and/or other national markets due to

Issue Theme Drug-Induced Liver Injury; Guest Editors, Naga Chalasani, MD, and Paul H. Hayashi, MD, MPH

hepatotoxicity.2,3 Hepatotoxic agents that were marketed in the United States, but then were removed or were severely restricted include iproniazid (1956), ticrynafen (1980), benoxaprofen (1982), bromfenac (1998), trovafloxacin (1998), and troglitazone (2000), reflecting fundamental shifts in the overall assessment by regulatory scientists of benefits and risks for these products.4,5 In addition, a sizable number of marketed products are labeled with boxed warnings or warnings and precautions concerning hepatotoxicity. Since 1995, warnings have been placed on more than 20 product labels due to hepatotoxicity.2,3,6–9 Because serious life-threatening DILI caused by most drugs is idiosyncratic and occurs only rarely in a treatment population, the presence of a drugspecific risk has often been recognized and confirmed only after exposure of a causative agent in a postmarket setting. This phenomenon is not surprising because typically in preapproval clinical trials only a few thousand study subjects are randomized to receive a study drug. Taking the challenge of DILI idiosyncrasy into account, over the past 15 years there has been a growing imperative for manufacturers and regulatory scientists to identify and characterize the hepatotoxic risk of new drugs as early as possible during drug

Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0034-1375961. ISSN 0272-8087.

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

1 Center for Drug Evaluation and Research, Food and Drug

DILI and Drug Development: A Regulatory Perspective development, to optimize regulatory decisions that concern their marketing approvability, product labeling, and/or postmarketing surveillance and risk management. From both a public health and financial cost perspective, it would be highly beneficial to accurately predict hepatotoxic risk of therapeutic products in postmarketing treatment populations from studies performed in advance to their consideration for market approval. Because preclinical biomarkers or predictive algorithms with sufficient predictive powers to exclude or reliably predict drug-specific hepatotoxic risk in patients have yet to be developed and qualified,10 regulatory authorities have focused considerable attention on critically important information that can be gathered from preapproval clinical trials to uncover and characterize DILI risk, as discussed below.

Range of DILI Phenotypes Several different drug-specific immunological and pharmacological mechanisms have been implicated in DILI.11,12 Therefore, it is no surprise that there is a broad set of clinical and histopathological signatures linked to drug-related hepatotoxicity. These have been conveniently grouped into categories that are marked by distinct prognostic inferences and associated regulatory considerations. Based on clinical criteria and serum test results, the acute forms of DILI linked to specific drugs, can often be categorized as hepatocellular, cholestatic or mixed.13,14 These broad groupings primarily reflect drug effects in hepatocytes, and in some cholestatic forms, biliary epithelial cells. Going a step further, there are several distinct subsets of drug-induced cholestasis.15,16 Bland cholestasis without inflammation resulting from highly selective pharmacological interference of bile transport in the apical membranes of hepatocytes is generally benign. In contrast, cholestatic and mixed forms of DILI that are accompanied by inflammation and necrosis of hepatocytes and/or biliary epithelial cells may lead in some instances to progression of hepatocellular or bile duct injury and a reduction of vital liver functions. Given these important differences in risk for serious outcomes, the matching of new drugs with specific hepatotoxic signatures in patients is an important step for regulatory scientists in characterizing their potential to cause serious liver injury. Other DILI phenotypes are also determined by the suspect drug, duration of exposure, and individual susceptibility factors. In rare instances, chronic injury with fibrosis may evolve, even after removal of the offending agent. Drugs that selectively block fatty acid β-oxidation, ATP synthesis or other mitochondrial functions have been linked to microvesicular steatosis.17 Drugs that cause an alcoholic hepatitis-like picture have been linked to cirrhosis. Certain antiviral agents with a potential to block mitochondrial DNA replication or transcription have been linked to drug-induced liver failure with lactic acidosis after a threshold period of exposure. Driven by individual susceptibility factors, several drugs have been identified that are associated with more than one phenotype of DILI.18 With these constraints and caveats, it follows that clinical trials will only have the potential to Seminars in Liver Disease

Vol. 34

No. 2/2014

Avigan reveal a true association of a study drug with DILI, if study protocols are adequately powered, enroll susceptible patients, and exceed a threshold period of exposure necessary for toxicity to occur. In addition, reliable risk assessment depends on a systematic approach in the complete acquisition and thorough interpretation of key information in all cases of significant liver injury.

Hepatocellular DILI in Clinical Trials There has been a growing awareness of the importance to systematically detect and characterize cases of acute hepatocellular injury in clinical trials. When caused by the study drug, the presence of this form of injury among study subjects can be a reliable harbinger of risk for life-threatening DILI in a larger postmarket treatment population. As previously described, a common characteristic of hepatocellular injuries induced by therapeutic drugs is their idiosyncratic nature. After acute hepatocellular injury is initiated by hepatotoxic drugs, the relative activities of competing downstream pathways will lead to either progression of organ injury or recovery, even in the face of continued drug exposure. Thus, DILI may either be self-limited or accelerate, in some instances to a state in which life-threatening losses of vital hepatocellular synthetic, metabolic, and transport functions will occur. Generally, clinical study subjects fall into one of three groups upon exposure to a drug that causes serious idiosyncratic hepatotoxicity.9,19 Most often, the largest group constitutes “tolerators” who manifest no toxicity. A smaller group is comprised of “adaptors” who develop transient mild hepatocellular toxicity with rises of serum liver aminotransferases that are self-limited, even in the face of continued treatment. Finally, an even smaller fraction of exposed individuals are “susceptibles” who are prone to developing progressive injury with loss of hepatocellular functions marked by jaundice and other sequelae of organ damage. At the most severe end of this spectrum are a few individuals who have accelerated loss of hepatocellular clearance and synthetic functions marked by liver failure with liver transplant or death as a possible outcome. The treatment-population-level distribution of these responses is determined both by a particular drug and the proportion of individuals who are prone to developing hepatotoxicity when exposed to the agent under recommended dosing conditions. It is curious that some drugs, when used in a recommended dose range, only cause mild transient forms of hepatocellular injury that always lead to adaptation and practically never or extremely rarely progress to clinically significant levels of liver damage. Notable examples include the heparins, acetaminophen, aspirin, statins, and tacrine.20–26 This is not the case with many other hepatotoxic agents associated with a wider spectrum of liver injury severity. Thus, accurately gauging a potential for new agents to cause clinically significant or more severe forms of liver injury is a key challenge that regulatory scientists currently face. To meet this challenge, there is a great need to develop reliable biomarkers that will indicate drugs that cause life-

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

216

threatening idiosyncratic hepatotoxicity in intended treatment populations, susceptible individuals who upon exposure to a specific drug (or class of drugs) will likely develop life-threatening DILI, and early liver injury events that with continued drug exposure will progress in severity rather than be marked by adaptation. With regards to markers of DILI susceptibility, recent progress has been made in the identification of a growing number of HLA class I and class II allelic variants in humans that enrich individuals who have developed episodes of DILI caused by specific drugs.27–33 Unfortunately, to date each of these markers alone has shown low positive predictive values, indicating that the future identification of other risk factors (e.g., genetic, epigenetic, and nongenetic elements) will also be critically important for the development of accurate predictive models for human DILI.34 With these gaps, DILI risk assessment of new therapeutic agents currently depends on careful iterative analyses of clinical data obtained throughout the pre- and postmarketing phases of the life-cycle of therapeutic agents. As previously emphasized, from a public health perspective an early comprehensive risk assessment using data systematically collected in preapproval phases is especially important, to optimally mitigate risk and preempt unintended postmarketing risk exposure. To establish standards for drug developers that are pertinent to optimal premarket DILI risk assessment, the FDA has issued a series of Guidances for Industry. These guidances, which are issued publically by the agency in draft and final forms, are not statutory rules or legally mandated requirements for drug manufacturers and developers. Rather, they describe FDA’s current views and enumerate suggestions and recommendations to consider. Several guidances have been cited in different sections of this article, all which may influence considerations by drug developers and clinical experts relevant to the assessment of DILI risk.

Lessons Learned from Earlier Clinical Trials Significance of Hy’s Law Cases In clinical trials, the presence of cases of acute hepatocellularinjury caused by the study drug that are marked by new elevations of both serum aminotransferases and bilirubin has proven to be a reliable sentinel of risk for life-threatening forms of DILI and liver failure in a large postmarket population treated with the study drug. This phenomenon originally dubbed by Robert Temple at the FDA as Hy’s law, in tribute to the late Hyman Zimmerman (remembered fondly by this author as an extraordinary clinical mentor and sharp-witted diagnostician), has central importance as a predictor of a drug’s potential to cause serious hepatotoxicity.35,36 Marked by elevations of serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) > 3
upper limit of normal (ULN) accompanied (or followed shortly afterwards) by raised bilirubin levels > 2
ULN, the presence of Hy’s law cases represent, at a minimum, intermediate levels of DILI severity. A key criterion for Hy’s law is that alternative causes of acute liver injury, other than the study drug, must be systematically

Avigan

excluded (e.g., acute viral hepatitis A, B, C, or E, concomitant use of other hepatotoxic agents, idiopathic autoimmune or alcoholic hepatitis, biliary tract disease, and circulatory disturbances, such as hypotensive events or right heart failure that may cause ischemic or hypoxic hepatopathy).37–39 Careful case evaluation by clinicians with an in-depth knowledge of diagnostic hepatology plays a critically important role in the appropriate acquisition and interpretation of clinical and diagnostic data. The 2009 FDA guidance entitled “DILI and Premarketing Clinical Evaluation” discusses these points extensively and contains a list of common competing causes of acute liver injury and associated diagnostic test indicators that can be used.40 In addition, it emphasizes the importance of developing comprehensive clinical narratives that incorporate pertinent time-linked diagnostic data of all clinically significant acute or worsening liver injury cases, including those with serum test abnormalities that conform to Hy’s law by knowledgeable clinicians. At least 10% of Hy’s law cases develop liver failure, even if the suspect drug is discontinued.37,41,42 In this respect, Hy’s law cases have prognostic significance. In addition, their presence indicates that the study drug would likely cause liver failure in other individuals, if used widely. It should be emphasized that cholestatic and mixed forms of DILI in clinical trials that have substantial rises in alkaline phosphatase (ALP) may be associated with serious clinical outcomes and must be also carefully evaluated in clinical trials.15,16 Nonetheless, Hy’s law specifically refers to druginduced hepatocellular injury marked by R values [ALT/ALP (fold ULN)] > 5 and ALP levels that are typically < 2
ULN. The importance of Hy’s law cases that are identified in preapproval clinical trials cannot be overstated. The 2009 Guidance points out that finding one Hy’s law case is worrisome. The specificity of two or more cases in a clinical trial database for predicting severe DILI in a larger treatment population is very high, with no examples, so far, where this has been refuted. Conversely, the absence of a Hy’s law case among a few thousand study subjects exposed to the study drug does not imply absence of risk. Although the “Rule-of-3 caps risk at a 95% probability level43 (e.g., 3,000 study subjects without a Hy’s law case implies that any risk for this event and drug-induced liver failure with death or liver transplant is less than 1/1,000 and 1/10,000, respectively), there are important caveats in its application. First, all study subjects must be accounted for, including study dropouts. Second, drug discontinuation rules may prevent what would otherwise have been severe outcomes in subjects with early DILI. Third, treatment protocols must have long enough study drug exposure for DILI to develop. Fourth, individuals with susceptibility to DILI must be enrolled in the studies. A characteristic of Hy’s law cases is that they typically arise from a larger subset of clinical study subjects receiving the study drug who develop milder forms of DILI marked by transient rises of serum aminotransferases with bilirubin levels that remain normal. Although the background prevalence of mild elevations of ALT may be raised in all study subjects in some randomized clinical trials due to the enrollment of individuals with pre-existing liver conditions (e.g., Seminars in Liver Disease

Vol. 34

No. 2/2014

217

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

DILI and Drug Development: A Regulatory Perspective

DILI and Drug Development: A Regulatory Perspective NASH and chronic viral hepatopathies), mild DILI signals would be reflected by imbalances in the percentages of subjects with elevations between study drug and placebo treatment groups.19 Thus, in assessing the DILI risk profiles of new drugs, regulatory scientists must systematically analyze liver test results of all study drug and comparator groups at a treatment population level as well as comprehensively review the clinical and diagnostic details surrounding individual cases with significant acute liver injuries. To enhance analysis and review of population and individual-level ALT and total bilirubin effects in clinical trials, John Senior and Ted Guo at the FDA have developed a two-step graphic tool using SAS/IntNet that has been dubbed eDISH.44–46 Peak serum ALT and bilirubin levels of each study subject are plotted as single points on a log-log graph containing four quadrants that are separated by boundaries of normal and elevated analyte levels. During inspection of these data, a reviewer can click on any single point to further investigate complete treatment time-line profiles of a subject of interest along with an accompanying clinical narrative and diagnostic test result information. The utility of eDISH is exemplified in an analysis performed by John Senior of tolvaptan-associated cases of liver injury that were observed in a pivotal clinical trial for autosomal dominant polycystic kidney disease (APKD).47 In the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) 3:4 trial 961 study subjects received tolvaptan at daily doses ranging between 60 mg to 120 mg, and 484 subjects received placebo.48 The eDISH analysis presented at a recent FDA advisory committee meeting47 revealed liver injury cases associated with exposure to tolvaptan. When selectively analyzed, some of these cases were determined to be causally linked to the study drug (►Figs. 1A and 1B). Establishing meaningful boundaries of normality of liver test analytes must take into account the upper limit of normal in the study population, the variability in the ranges of test results from different laboratories, and importantly, the impact that pre-existing liver test abnormalities have on the detection of liver signals during treatment with study drugs. There is a growing consensus that each individual’s pretreatment or during-treatment nadir baseline measures establish an appropriate frame of reference for signals of superimposed acute liver injury that may be drug-induced.39,46,49,50 To meet this challenge, modifications of eDISH are currently being considered that would enable reviewers to custom-fit appropriate boundaries on the graphic x–y plots, to optimize the demarcation of liver test results that point to a superimposed acute liver injury.

Regulatory Actions due to DILI in Different Countries In contending with new drugs that have a hepatotoxic profile, FDA regulatory actions will be affected by several important considerations. These include the estimated rates of lifethreatening hepatotoxic adverse events among treated patients in the postmarket, the presence (or absence) of equivalent available treatments for the treated disease that are FDA-approved, the presence (or absence) of effective tools to mitigate DILI risk in treated patients, and an overall benefits Seminars in Liver Disease

Vol. 34

No. 2/2014

Avigan

Fig. 1 Application of eDish to facilitate the stepwise identification andcharacterization of DILI signals in the Tolvaptan Efficacy and Safetyin Management of Autosomal Dominant Polycystic Kidney Disease and itsOutcomes (TEMPO) 3:4 trial (the pivotal clinical trial of tolvaptan for the treatment of autosomal dominant polycystic kidney disease; Courtesy of J. Senior). In the controlled study, 961 study subjects received tolvaptan at daily doses ranging between 60 mg to 120 mg, and 484 subjects received placebo. (A) Peak values of serum alanine aminotransferase activity (ALT, IU/L) and serum total bilirubin concentration (TBL, mg/dL) are plotted on an x–y plot as values x ULN on log 10 scales, showing results from all 1,445 subjects in the study (X ¼ experimental drug; C ¼ control drug). Data of subjects who received tolvaptan (Δ) or placebo (O) who are of interest are selected by clicking on symbol to retrieve a time course graph of serum test results and other relevant diagnostic information. In the eDISH plot, there is a preponderance of individuals treated with the study drug in the Hy’s law and Temple’s corollary ranges, compared with placebo. (B) Time course of serum test results (ALT, AST, ALP, and TBL) recorded as values x ULN on a log 10 scale for a study subject of interest. In this example, a 50-year-old Japanese woman who was started on tolvaptan at a daily dose of 60 mg that was subsequently increased to 120 mg developed high elevations of serum aminotransferases (AT) by day 162 of treatment; a liver biopsy was consistent with a pattern of hepatocellular injury associated with DILI. After discontinuation of tolvaptan, the AT levels normalized. These abnormalities rapidly recurred after reintroduction of tolvaptan. ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; TBL, total bilirubin; ULN, upper limit of normal.

and risks assessment of the candidate drug. Reflecting earlier lessons drawn with the withdrawals from U.S. marketing of bromfenac51 in 1998 and troglitazone52–56 in 2000, there have been several more recent NDAs that did not win FDA approval because of hepatotoxicity observed in clinical trials. In addition, subsequent market removals of FDA-approved therapeutic products from the U.S. market have not transpired due to DILI. Ximelagatran, a direct thrombin inhibitor, was developed both for long-term use (secondary prevention of venous thromboembolism and prevention of atrial fibrillation-associated thromboembolic events) and short-term

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

218

management of postoperative thromboembolic risk after total knee replacement.57 Despite the absence of ximelagatran-induced hepatotoxicity in preclinical animal models, among 6,948 patients treated with ximelagatran in the long-term clinical trials, 7.6% and 1.1% developed serum ALT increases > 3
and 10
ULN, respectively. More importantly, 0.5% of these study subjects also developed concurrent increases of total bilirubin > 2
ULN, compared with 0.08% in the comparator warfarin treatment arms. Among the 37 ximelagatran-associated cases (13 of which had no alternative etiologic explanation) there were three deaths linked to liver injury.58 A comprehensive review revealed that ximelagatran-induced serious hepatotoxicity with rapid accelerated injury was highly likely a cause in one of the three deaths. With these findings, and in the absence of convincing data to support the utility of routine long-term serum liver test monitoring to mitigate DILI risk in all patients chronically treated with ximelagatran, in 2004 the initial NDA was not approved by FDA. Of interest, ximelagatran was approved and marketed in 22 other countries, but withdrawn by the manufacturer from all markets in 2006 due to the emergence of a case of severe hepatotoxicity in an orthopedic surgery trial during extended treatment over 35 days.59 Similarly, lumiracoxib, a COX-2 inhibitor was found to cause idiosyncratic DILI in clinical trials. In the Therapeutic Arthritis Research and Gastrointestinal Events Trial (TARGET), among 9,117 patients randomized to receive lumiracoxib 2.6% developed serum ALT elevations greater than 3
ULN, compared with 0.6% in the naproxen or ibuprofen treatment arms.30,60 Among the cases of liver injury associated with lumiracoxib, nine showed biochemical profiles consistent with Hy’s law. In addition, there were cases with increasing serum levels of ALT greater than 5
, 8
, 10
, 15
, and 20
ULN. With these findings and the domestic availability of other COX-2 inhibitors not linked to such a high risk for serious hepatotoxicity, lumiracoxib was not approved in the United States. However, it was approved and marketed in several other countries. In 2007, Australia’s Therapeutic Goods Administration (TGA) received eight reports of serious liver injury associated with lumiracoxib, including two deaths and two liver transplants.61 With the emergence of postmarketing reports of serious DILI, several of these countries withdrew approval of the Cox-2 inhibitor in 2007 and 2008. As mentioned above, the availability of another product(s) for the treatment of a disease displaying a similar mechanism of action and equivalent efficacy with a new idiosyncratic hepatotoxic drug has impacted the calculus of benefits and risks. One historical example of such a scenario is the assessment of troglitazone, a thiazolidinedione. When it was approved in 1997 in the United States, this agent was the first in a class of peroxisome-proliferator-activated receptor gamma agonists. By the time it was removed from the U.S. market 3 years later with close to 100 associated postmarketing cases of acute liver failure, two other thiazolidinediones that proved to be significantly less hepatotoxic (pioglitazone and rosiglitazone) had gained marketing approval.62 It should be noted that there are differences of regulatory tools for postmarketing regulatory oversight and interven-

Avigan

tions that are available to regulatory authorities and scientific agencies in different countries which may contribute to differences between countries in decisions taken concerning market approval of new drugs. For example, in contrast to the United States, where normal market approval is not timelimited, the initial market authorization for newly approved products by the European Medicines Agency (EMA) is valid only for 5 years and must be renewed after the first cycle through reapplication by the Marketing Authorization Holder.63 In some situations, when there is a special concern, initial marketing authorization may be “conditional” and last only one year at a time before application for renewal is required.64 Such procedures in the European Union provide a probationary format for time-linked reviews of postmarket drug-related outcomes. The FDA has an increasingly important role to play in encouraging manufacturers to develop innovative drugs that will fill unmet medical needs and/or provide meaningful advantages in the treatment of serious conditions, including several infectious diseases, hereditary conditions, and malignancies. Expedited programs to enhance the agency’s role in this arena are described in a recently released draft guidance.65 In the development of drugs to address such unmet medical needs for serious conditions, in instances where benefits appear to outweigh risks, drugs with a hepatotoxic profile might be approved by the agency. To manage risk for DILI associated with such agents, it will be necessary to educate practitioners in the importance of adequately following and assessing patients during treatment and respond promptly to the advent of hepatotoxicity with appropriate modifications of treatment. One example of a newly marketed agent in this category is ipilimumab, the first in a class of anti-CTLA-4 monoclonal antibodies that was approved in 2011 for the treatment of unresectable or metastatic melanoma.66 This agent stimulates cytotoxic T lymphocytes (CTLs) in a polyclonal fashion, including those with pronounced antitumor activity.67,68 With such a mechanism at play, it is not surprising that ipilimumab also displays a wide range of immune-mediated toxicities. Among 540 patients who received this agent in a randomized clinical trial, several lifethreatening immune-mediated adverse events were observed.69 These included enterocolitis (7%), serious hepatitis (2%) and fatal hepatic failure (0.2%), as well as severe reactions involving other organs. Ipililumab’s product labeling recommends the monitoring of liver tests and clinical assessment for signs and symptoms of hepatotoxicity before each of four successive 3-weekly doses, with an instruction to rule out nondrug causes in the face of acute liver injury.66 Using experience from the clinical trial as a guide, there are also labeling instructions to permanently discontinue the agent with new serum ALT elevations > 5
ULN or rises of bilirubin, in conjunction with the administration of systemic corticosteroids.

Postmarketing DILI Risk Assessment The assessment of DILI risk attached to new drugs and biological agents is an iterative process. Because clinically Seminars in Liver Disease

Vol. 34

No. 2/2014

219

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

DILI and Drug Development: A Regulatory Perspective

DILI and Drug Development: A Regulatory Perspective serious idiosyncratic DILI often is rare, accurate measures of risk often depend on the integration of pre- and postmarketing sources of information, using a variety of methods.70 After the approval of a new drug, with clinical trial data in hand, postapproval data sources that support DILI risk assessment include the FDA Adverse Events Reporting System (FAERS),71–73 published DILI case reports that are peer-reviewed, DILI registries,37,41,42,74 epidemiological observational and case-control studies,75,76 and Sentinel.77,78 Each of these datastreams is marked by inherent benefits, limitations, and opportunities with regards to the reliable capture and characterization of DILI cases, their generalizability on a national level and the identification of demographic and other idiosyncratic determinants of susceptibility to liver injury caused by a particular drug (►Table 1).9,76 With all of these approaches and methods comprehensive and complete clinical narratives that incorporate time-linked diagnostic data over the course of each event are vital to enable accurate assessment of liver injury phenotypes, severity, and causality. Critically important data elements for complete DILI reports have been summarized by the NIH Drug-Induced Liver Injury Network (DILIN).79 Methods to assess the likelihood of a causal association of a post-marketing liver injury with a suspect drug can employ algorithmic criteria, expert opinion, or Bayesian operations (►Table 2).9,38,80 Although from a regulatory perspective it would be ideal to utilize an approach that is easily applied and uniformly reliable, in the absence of a gold-standard frame of reference each of the aforementioned methods has both inherent advantages and disadvantages. Algorithmic methods such as the Roussel Uclaf Causality Method (RUCAM)81–85 and the Maria and Victorino (M&V)86 Scale have been extensively discussed elsewhere. In brief, they compute aggregate scores using a composite of domains, each weighted with a fixed range of possible points that are individually scored. New molecular entities with little prior exposure in the population may be associated with unexpected or unusual DILI signatures, susceptibility factors, and/or mechanisms of toxicity. In this circumstance, algorithmic approaches that utilize rigid clinical and laboratory scoring criteria often fall short and do not accurately assess likelihood of drug-induced liver injury. Moreover, in one recent study performed by NIH DILIN reviewers, test-retest and inter-rater reliabilities of RUCAM were low.83,84 To avoid these pitfalls, several academic groups and regulatory scientists at the FDA, have developed processes for causality adjudication by experts who weigh the relative values of both available and missing diagnostic data, as well as evolving scientific information.74,87 For this purpose, the FDA has used a five-level categorical scale of clinical severity and likelihood of causal association developed by the NIH DILIN.9 Finally, Bayesian methods have been applied to derive quantitative probabilities of causality in individual cases of liver injury.88–91 These employ conditional probabilities that are based on results derived from a variety of other datasets. Until there is further progress to reliably confirm, weigh, and integrate measurements from multiple sources and disciplines, it is likely that Bayesian methods will only be applied as tools of research. Seminars in Liver Disease

Vol. 34

No. 2/2014

Avigan

Recent Initiatives to Improve Postmarketing Surveillance and Assessment of DILI Setting Standards for Case Reports Drug-induced liver injury case reports that are entered into FAERS or published in peer-reviewed journals are sent on a voluntary basis by heath care professionals (HCPs) or other stakeholders. Often submitted spontaneous DILI reports are incomplete and lack evidence that is needed to accurately characterize the clinical signature, course, and severity of liver injury and systematically exclude alternative causes. MedWatch reporting need only provide an identifiable patient, an identifiable reporter, an adverse event, and identify exposure to a suspect agent.92,93 Although data-mined measures of disproportionate reporting in the FAERS database may provide a useful screen for early signals of liver injury associated with newly marketed drugs, the characterization of causality must be determined through careful analysis of individual cases to exclude other etiologies of liver injury.62 Thus, the inclusion in MedWatch reports of diagnostic test results with informative narratives containing all the key data elements that are necessary to assess drug exposures, characterize liver injury events, as well as evaluate causality, is essential for optimal risk analysis by FDA reviewers. To address current deficiencies in peer-reviewed postmarketing reports of DILI, the Liver Disease Research branch in the National Institute of Diabetes and Digestive and Kidney Diseases together with the National Library of Medicine have developed LiverTox, a web-based repository of DILI information.94 The website that went live on April 2012 provides a comprehensive list of Important Elements in Reporting DILI, accompanied by a convenient checklist in the reporting of a potential case. Standards surrounding required data elements for reporting potential postmarketing cases of DILI have also been established in several international workshops.13,37,81 In the premarketing arena, data elements for possible DILI cases similar to these have been proposed for the Assessment of DILI in Clinical Trials at a Workshop on Liver Safety Assessment in Clinical Drug Development that was held in Boston in 2012.39

Sentinel Project In May 2008, the U.S. Department of Health and Human Services and the FDA launched the Sentinel Initiative, an active surveillance system to monitor the safety of drugs using a very large distributed database of electronic health care data in the United States.77,78,95 Currently, Sentinel covers over 125 million lives, although the database is not nationally representative because certain patient populations are not included (e.g., uninsured individuals and inpatients). In the distributed system of multiple health care data partners, millions of patient records remain in their individual secure environments, but provide data for a coordinating center that can aggregate and analyze drug safety signals across databases in near real-time on behalf of the FDA or other stakeholders. To interrogate Sentinel for drug safety signals, patient-level clinical and laboratory coded events can be cross-indexed with the individual’s exposure to a specific

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

220

DILI and Drug Development: A Regulatory Perspective

Avigan

221

Data sources

Examples

Benefits

Limitations

Opportunities

Randomized clinical trials

Phase III studies in drug development programs

Hy’s law cases predictive of study drug DILI risk liability. Can also cap risk when adverse events are absent (“Rule of 3”).

Insufficient statistical power to detect very rare events. Short period treatment protocols can underestimate risk marked by latency. Isolated aminotransferase elevations not predictive of serious DILI.

Employ good practices for study subject monitoring & assessment. Use clinical experts to evaluate liver injuries.

Spontaneous report databases

FAERS VigiBase

Large repositories of reports for postmarketing DILI signaling. Measures of disproportionate reporting of adverse events can be performed in realtime (drug utilization data not required).

Gross under-reporting. Insufficient information in reports. Underlying conditions & concomitant drugs are confounders. Cannot measure DILI incidence or frequency.

Report all important clinical & diagnostic elements. Describe time-linked data in narratives.

Peer-reviewed case report(s)

Journal articles with DILI cases.

Clinical DILI signatures and diagnostic tests typically provided in publications.

Inconsistent report quality. Variable case ascertainment. Publication biases & delays.

Use checklists for full clinical & diagnostic evaluations.

Registries

DILIN ALFSG Networks in Spain, Korea, Sweden, Japan

Structured clinical & diagnostic assessments. Real-world sampling of suspect DILI cases.

Enrollees reflect referral system biases. No denominators of drug utilization or incidence measures.

Report all cases to FDA & appropriate public health authorities.

Observational Studies

UnitedHealth Group, HMO Research Network

Linkages of adverse events and drug exposures to medical records enable investigations of diagnostic tests & clinical outcomes.

DILI cases only accrue after sufficient uptake of suspect drug. Claims database studies depend on consistent coding practices & low health care plan enrollee turnover. Point estimates of incidence of rare DILI cases have wide confidence intervals.

Link all suspect drug exposures with all cases of serious liver injury. Assess medical records & laboratories with expert clinicians.

Case-control Studies

GPRD (UK)

Only cases of liver injury or DILI & controls exposed to a suspect drug(s) selected for enrollment.

No links to study population drug utilization, DILI incidence or absolute risk. DILI case documentation sometimes limited.

Document all DILI case details (e.g., risk factors demographics, causality & outcomes).

Sentinel

Pilot Studies in MiniSentinel & OMOP.

Very large ’convenience’ sample in U.S., currently with >125 million covered lives.

Not projectable to U.S. population. Code-based strategies to identify DILI cases in the distributed database not yet established. Routine links to patient medical records not fully implemented.

Strategize to identify all cases of serious liver injury exposed to suspect drug & link to all case records.

Abbreviations: DILI, drug-induced liver injury; FDA, U.S. Food and Drug Administration; HMO, health maintenance organization; GPRD, General Practice Research Database; OMOP, Observational Medical Outcomes Partnership.

list of medications. With FDA support, two pilot initiatives, Mini-Sentinel96 and the Observational Medical Outcomes Partnership97 (a collaboration of federal systems) have been established to test pharmacovigilance methods, develop prototype activities and lay groundwork for the Sentinel system. As a first exercise in detecting signals of acute liver injury in Mini-Sentinel, the positive predictive values (PPV) of single and combinations of ICD-9 codes to identify severe

acute liver injury (SALI) were tested against a sample of available medical records of hospitalized patients with and without pre-existing liver disease adjudicated by experts.98 Single ICD-9 codes consistent with hepatic necrosis showed poor PPV, whereas combinations of these codes with liver disease sequelae (e.g., hepatorenal syndrome, hepatic encephalopathy, etc.) showed the highest PPVs, at the expense of missing some SALI events (reduced sensitivity). From these Seminars in Liver Disease

Vol. 34

No. 2/2014

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Table 1 Data streams that inform DILI risk assessment for specific marketed drugs

Seminars in Liver Disease

RUCAM; M&V.

NIH DILIN & FDA likelihood tiers; Visual analog scales.

Studies comparing methods to assess causality of liver injury.

Algorithmic

Vol. 34

Expert opinion

No. 2/2014

Bayesian approaches

These systems incorporate evolving scientific information and are flexible. They are especially useful for new drugs.

The computations of quantitative probabilities of DILI are datadriven.

Probabilistic methods use conditional probabilities and are influenced by ’priors’.

The award & penalty points are linked to objective measures.

Strengths

Categorical or continuous scales weigh the relative values of available & missing information.

Scalar scoring systems are based on pre-specified ranges of award & penalty points in fixed domains that inform the likelihood of causal association.

Criteria

Advanced statistical treatments are required. Reliable diagnostic data representing many cases of liver injury across multiple data sources are difficult to acquire.

The ratings among experts are not uniform. Although discussion is necessary to achieve consensus, the interactive dynamics among raters may cause bias.

The criteria for assigned points are not optimal for certain DILI clinical phenotypes (e.g., times to onset & resolution), clinical decisions (e.g., re-challenge), concomitant drugs or alcohol use. DILI risk factors may not be reliably ascertained. Evolving & new predictors are not incorporated into the scales. The single rater test-retest & inter-rater scoring reliabilities are low.

Limitations

Tools for academic research

Clinical expert adjudication of cases in clinical trials or registries

Practitioner assessments of liver injury cases in clinical practice

Applicable settings

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

DILI and Drug Development: A Regulatory Perspective

Abbreviations: DILI, drug-induced liver injury; DILIN, DILI Network; FDA, U.S. Food and Drug Administration; M&V, Maria and Victorino Scale; RUCAM, Roussel Uclaf Causality Method.

Examples

Methods

Table 2 Assessment of causal association of liver injury with a suspect drug

222 Avigan

DILI and Drug Development: A Regulatory Perspective

programs, the FDA has recently also issued a companion draft guidance that outlines key steps that must be undertaken by sponsors for biomarker qualification.106.

Disclaimer The views expressed are those of the author and do not necessarily represent the position of, nor imply endorsement from, the U.S. Food and Drug Administration or the U.S. Government.

DILI Biomarker Development Although there are significant challenges, predictive DILI biomarkers could be developed to identify individuals with increased susceptibility to drug-specific DILI, cases of early DILI that are destined to progress to serious injury with continued drug exposure, or drugs that will cause serious DILI in a large exposure population.9 Even in the face of diverse drug-related pathways of liver injury and multiple mechanisms of individual susceptibility, there is a growing consensus that the discovery and validation of new predictors of DILI will provide valuable aids in drug development and risk management. Several postmarket ADR and DILI consortia for biospecimen collection have been established in the United States and other countries to enable biomarker investigations using case-control study designs.99 The development of universal standards for the systematic collection and documentation of genomic (buccal or white blood cells) and metabonomic (serum and urine) and/or proteomic (serum) biospecimens from study subjects with acute liver injury as well as controls, across preapproval clinical trials of potentially hepatotoxic agents has been proposed.39 In 2013, the FDA issued a new guidance on the premarket evaluation of clinical pharmacogenomics during early-phase clinical studies.100 This guidance describes situations when DNA should be collected and banked, and when genomic studies should be conducted to identify markers for differential responses in study subjects, including ADR susceptibility. It has been envisioned that information derived from such databases could be pooled and shared widely among stakeholders in a precompetitive space.101 Toward this goal, the FDA and the EMA have separately initiated recent public discussions on new proposals for expanding access to participant-level clinical trial data, taking into account a vital need for the protection of personal data and commercially confidential information.102–104

References 1 Meadows M. Promoting Safe and Effective Drugs for 100 years.

2

3

4

5

6

7

8

9

10

Biomarker Qualification by The Food and Drug Administration To promote the development of clinical efficacy or safety predictors (including DILI markers) that can be used to facilitate drug development in clinical trials, the FDA has developed a program, outlined in a draft guidance, for Voluntary Genomic Data Submissions.105 These submissions are meant to serve as a focal point for informal meetings between investigators and FDA scientists to guide further development and analysis of the performance characteristics and generalizability of candidate biomarkers. With an interest to promote the development of improved or more reliable single or composite predictors of efficacy and safety of new agents across drug development

223

11 12 13

14

2006. Available at: http://www.fda.gov/AboutFDA/WhatWeDo/ History/CentennialofFDA/CentennialEditionofFDAConsumer/ ucm093787.htm. Accessed September 20, 2013 Chen M, Vijay V, Shi Q, Liu Z, Fang H, Tong W. FDA-approved drug labeling for the study of drug-induced liver injury. Drug Discov Today 2011;16(15-16):697–703 Liver Toxicity Knowledge Database (LTKB) Benchmark Dataset. National Center for Toxicological Research. U.S. Food and Drug Administration (FDA). Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/LiverToxicityKnowledgeBase/ ucm226811.htm. Accessed September 20, 2013 Temple RJ. Welcome to DILI. AASLD-FDA Annual Meeting on Drug-Induced Liver Injury, March 2011. Available at: http:// www.aasld.org/meetings/Documents/Hepatotoxicity%20STC/01_Temple.pdf. Accessed September 13, 2013 Qureshi ZP, Seoane-Vazquez E, Rodriguez-Monguio R, Stevenson KB, Szeinbach SL. Market withdrawal of new molecular entities approved in the United States from 1980 to 2009. Pharmacoepidemiol Drug Saf 2011;20(7):772–777 Stevens JL, Baker TK. The future of drug safety testing: expanding the view and narrowing the focus. Drug Discov Today 2009;14(34):162–167 Watkins PB, Bloom J, Hunt C. Biomarkers of acute idiosyncratic hepatocellular injury in clinical trials. In: Olson S, Robinson S, Giffin R, eds. Accelerating the Development of Biomarkers for Drug Safety: Institute of Medicine Workshop Summary. San Diego, CA: Academic Press; 2009:Chapter 5,42–57 MedWatch. The FDA Safety Information and Adverse Event Reporting Program. Available at: http://www.fda.gov/safety/ MedWatch/default.htm. Accessed September 20, 2013 Avigan MI. Regulatory perspectives. In: Kaplowitz N, Deleve LD, eds. Drug-Induced Liver Disease. 3 rd ed. London, UK: Academic Press; 2013:689–712 Avigan MI. Finding predictive biomarkers: Can we harmonize across clinical trials? AASLD-FDA Annual Meeting on Drug-Induced Liver Injury, March 2013. Available at: http://www.aasld. org/dili/Documents/2013/4A_1_M_Avigan-n.pdf. Accessed September 20, 2013 Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov 2005;4(6):489–499 Tujios S, Fontana RJ. Mechanisms of drug-induced liver injury: from bedside to bench. Nat Rev Gastroenterol Hepatol 2011;8(4):202–211 Aithal GP, Watkins PB, Andrade RJ, et al. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther 2011;89(6):806–815 Senior JR, Avigan M. Detection of hepatotoxicity during drug development: practical problems and regulatory measures. In: Andrade RJ, ed. Hepatotoxicity. Arroyo V, ed. International Hepatology Updates. Barcelona: Permanyer Publications; 2007: 147–166 Seminars in Liver Disease

Vol. 34

No. 2/2014

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

early data, it is evident that reliable algorithms for routine screens of Sentinel for serious DILI are not yet available. To establish a fully capable system, it will be necessary to accurately filter millions of medical records to identify the subset of records with serious liver injury that are associated with exposure to a suspect drug. These must then be individually analyzed to determine case-level clinical characteristics and causality.

Avigan

DILI and Drug Development: A Regulatory Perspective

Avigan

15 Padda MS, Sanchez M, Akhtar AJ, Boyer JL. Drug-induced chole16

17

18

19

20

21

22

23

24

25 26 27

28

29

30

31

32

33

34

35 36 37

stasis. Hepatology 2011;53(4):1377–1387 Kullack-Ublick GA. Drug-induced cholestatic liver disease. In: Trauner M, Jansen P, eds. Molecular Pathogenesis of Cholestasis. Austin, TX: Landes Bioscience; 2003 Kaplowitz N. Drug-induced liver injury, introduction and overview. In: Kaplowitz N, Deleve LD, eds. Drug-Induced Liver Disease. 3 rd ed. London, UK: Academic Press; 2013:3–14 Phenotypes of Drug-Induced Liver Injury. LiverTox. Available at: http://www.livertox.nih.gov/Phenotypes_intro.html. Accessed September 19, 2013 Watkins PB, Seligman PJ, Pears JS, Avigan MI, Senior JR. Using controlled clinical trials to learn more about acute drug-induced liver injury. Hepatology 2008;48(5):1680–1689 Olsson R, Korsan-Bengtsen B-M, Korsan-Bengtsen K, Lennartsson J, Waldenström J. Serum aminotransferases after low-dose heparin treatment. Short communication. Acta Med Scand 1978; 204(3):229–230 Harrill AH, Roach J, Fier I, et al. The effects of heparins on the liver: application of mechanistic serum biomarkers in a randomized study in healthy volunteers. Clin Pharmacol Ther 2012;92(2): 214–220 Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA 2006;296(1):87–93 Watkins PB, Zimmerman HJ, Knapp MJ, Gracon SI, Lewis KW. Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. JAMA 1994;271(13):992–998 Product label for Zocor (simvastatin). Approved October 6, 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019766s083lbl.pdf. Accessed September 20, 2013 Russo MW, Scobey M, Bonkovsky HL. Drug-induced liver injury associated with statins. Semin Liver Dis 2009;29(4):412–422 Chalasani N. Statins and hepatotoxicity: focus on patients with fatty liver. Hepatology 2005;41(4):690–695 Hautekeete ML, Horsmans Y, Van Waeyenberge C, et al. HLA association of amoxicillin-clavulanate—induced hepatitis. Gastroenterology 1999;117(5):1181–1186 O’Donohue J, Oien KA, Donaldson P, et al. Co-amoxiclav jaundice: clinical and histological features and HLA class II association. Gut 2000;47(5):717–720 Kindmark A, Jawaid A, Harbron CG, et al. Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenomics J 2008;8(3):186–195 Singer JB, Lewitzky S, Leroy E, et al. A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury. Nat Genet 2010;42(8):711–714 Daly AK, Donaldson PT, Bhatnagar P, et al; DILIGEN Study; International SAE Consortium. HLA-B5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 2009;41(7):816–819 Hirata K, Takagi H, Yamamoto M, et al. Ticlopidine-induced hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary casecontrol study. Pharmacogenomics J 2008;8(1):29–33 Spraggs CF, Budde LR, Briley LP, et al. HLA-DQA102:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. J Clin Oncol 2011;29(6):667–673 Avigan MI. Key features of DILI biomarkers we need. AASLD-FDA Annual Meeting on Drug-Induced Liver Injury, March 2012. Available at: http://www.aasld.org/dili/Documents/2012/3A1_AviganN.pdf. Accessed September 20, 2013 Temple R. Hy’s law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf 2006;15(4):241–243 Reuben A. Hy’s law. Hepatology 2004;39(2):574–578 Fontana RJ, Seeff LB, Andrade RJ, et al. Standardization of nomenclature and causality assessment in drug-induced liver injury:

Seminars in Liver Disease

Vol. 34

No. 2/2014

38 39

40

41 42

43 44

45

46

47

48

49

50

51

52

53

54

summary of a clinical research workshop. Hepatology 2010; 52(2):730–742 Hayashi PH. Causality assessment in drug-induced liver injury. Semin Liver Dis 2009;29(4):348–356 Avigan MI, Bjornsson EI, Pasanen M, et al. Required data elements and best practices for data collection and standardization. Conference Report: Workshop on Liver Safety Assessment in Clinical Drug Development. Drug Saf 2014; In Press FDA Guidance for Industry. Drug-induced liver injury: Pre-marketing clinical evaluation. July 2009. Available at: http://www.fda. gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf. Accessed September 20, 2013 Björnsson E, Olsson R. Outcome and prognostic markers in severe drug-induced liver disease. Hepatology 2005;42(2):481–489 Andrade RJ, Lucena MI, Fernández MC, et al; Spanish Group for the Study of Drug-Induced Liver Disease. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005;129(2): 512–521 Rosner B. The binomial distribution. In: Rosner B, ed. Fundamentals of biostatistics. Belmont, CA: Duxbury Press; 1995:82–85 Gelperin K, Guo T, Senior J. A simple tool for finding important cases in a clinical trial. AASLD-FDA Annual Meeting on DrugInduced Liver Injury, March 2008. Available at: http://www.fda. gov/downloads/Drugs/ScienceResearch/ResearchAreas/ ucm076777.pdf. Accessed September 20, 2013 Watkins PB, Desai M, Berkowitz SD, et al. Evaluation of druginduced serious hepatotoxicity (eDISH): application of this data organization approach to phase III clinical trials of rivaroxaban after total hip or knee replacement surgery. Drug Saf 2011;34(3): 243–252 Senior J. Evolution of the Food and Drug Administration approach to liver safety assessment for new drugs: Current status and challenges. Conference report: Workshop on Liver Safety Assessment in Clinical Drug Development. Drug Saf 2014; In press Senior JR. Hepatic safety of tolvaptan. In: FDA Briefing Document; Center for Drug Evaluation and Research Advisory Committee Meeting Briefing. August 5, 2013:183–208. Available at: http:// www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM363343.pdf. Accessed September 28, 2013 Torres VE, Chapman AB, Devuyst O, et al; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012;367(25): 2407–2418 Seeff L. Drug-induced liver injury in persons with pre-existing liver disease. AASLD-FDA Annual Meeting on Drug-Induced Liver Injury, March 2013. Available at: http://www.aasld.org/ dili/Documents/2013/2A_4_L_Seeff-n.pdf. Accessed September 20, 2013 Kullak-Ublick GA, Merz M, Griffel L, Kaplowitz N, Watkins P. Liver safety assessment in special populations (hepatitis B, C, and oncology trials). Conference report: Workshop on Liver Safety Assessment in Clinical Drug Development. Drug Saf 2014; In Press Goldkind L, Laine L. A systematic review of NSAIDs withdrawn from the market due to hepatotoxicity: lessons learned from the bromfenac experience. Pharmacoepidemiol Drug Saf 2006;15(4): 213–220 Knowler WC, Hamman RF, Edelstein SL, et al; Diabetes Prevention Program Research Group. Prevention of type 2 diabetes with troglitazone in the Diabetes Prevention Program. Diabetes 2005; 54(4):1150–1156 Graham DJ, Drinkard CR, Shatin D. Incidence of idiopathic acute liver failure and hospitalized liver injury in patients treated with troglitazone. Am J Gastroenterol 2003;98(1):175–179 Gitlin N, Julie NL, Spurr CL, Lim KN, Juarbe HM. Two cases of severe clinical and histologic hepatotoxicity associated with troglitazone. Ann Intern Med 1998;129(1):36–38

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

224

Avigan

55 Graham DJ, Green L, Senior JR, Nourjah P. Troglitazone-induced

73 Lee WM, Senior JR. Recognizing drug-induced liver injury: cur-

liver failure: a case study. Am J Med 2003;114(4):299–306 Herrine SK, Choudhary C. Severe hepatotoxicity associated with troglitazone. Ann Intern Med 1999;130(2):163–164 He R. Clinical review of Exanta (ximelagatran) tablets. 2004. Available at: http://www.fda.gov/ohrms/dockets/ac/04/briefing/ 2004-4069B1_04_FDA-Backgrounder-MOR-180.pdf. Accessed September 20, 2013 Avigan M. Case Study: Ximelagatran hepatotoxicity. AASLD-FDA Annual Meeting on Drug-Induced Liver Injury. January 2005. Available at: http://www.fda.gov/downloads/Drugs/ScienceResearch/.../ucm080355.ppt. Accessed September 20, 2013 EMEA press release. AstraZeneca withdraws its application for ximelagatran 36-mg film-coated tablets. London, February 16, 2006. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2010/02/WC500074073.pdf. Accessed September 20, 2013 Klickstein L. Therapeutic Arthritis Research and Gastrointestinal Events Trial (TARGET). AASLD-FDA Annual Meeting on DrugInduced Liver Injury, March 2012. Available at: http://www. aasld.org/dili/Documents/2012/2A-2_KlicksteinN.pdf. Accessed September 20, 2013 Lumiracoxib (Prexige). Urgent advice regarding management of patients. Australian Government, Therapeutic Goods Administration. August 13, 2007. Available at: http://www.tga.gov.au/ safety/alerts-medicine-lumiracoxib-070813.htm. Accessed September 20, 2013 Brinker AD, Lyndly J, Tonning J, Moeny D, Levine JG, Avigan MI. Profiling cumulative proportional reporting ratios of drug-induced liver injury in the FDA Adverse Event Reporting System (FAERS) database. Drug Saf 2013;36(12):1169–1178 European Medicines Agency. Guideline on the processing of renewals in the centralised procedure. June 22, 2012. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/ Regulatory_and_procedural_guideline/2012/03/WC500124501. pdf. Accessed September 20, 2013 European Medicines Agency post-authorisation procedural advice for users of the centralised procedure. July 2013. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/ Regulatory_and_procedural_guideline/2009/10/WC500003981. pdf. Accessed September 20, 2013 FDA Draft Guidance for Industry. Expedited Programs for Serious Conditions – Drugs and Biologics. June 2013. Available at: http:// www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf. Accessed September 20, 2013 Ipilimumab FDA-approved product label. 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/ 125377s0000lbl.pdf. Accessed September 20, 2013 Weber J. Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. Oncologist 2007;12(7):864–872 Hoos A, Ibrahim R, Korman A, et al. Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy. Semin Oncol 2010;37(5):533–546 Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363(8):711–723 Weaver J, Willy M, Avigan M. Informatic tools and approaches in postmarketing pharmacovigilance used by FDA. AAPS J 2008; 10(1):35–41 Weaver J, Grenade LL, Kwon H, Avigan M. Finding, evaluating, and managing drug-related risks: approaches taken by the US Food and Drug Administration (FDA). Dermatol Ther 2009;22(3): 204–215 Ahmad SR, Goetsch RA, Marks NS. Spontaneous Reporting in the United States. In: Strom BL, ed. Pharmacoepidemiology. 4th ed. West Sussex, England: John Wiley & Sons, Ltd.; 2005:135–159

rent problems, possible solutions. Toxicol Pathol 2005;33(1): 155–164 Fontana RJ, Watkins PB, Bonkovsky HL, et al; DILIN Study Group. Drug-Induced Liver Injury Network (DILIN) prospective study: rationale, design and conduct. Drug Saf 2009;32(1):55–68 de Abajo FJ, Montero D, Madurga M, García Rodríguez LA. Acute and clinically relevant drug-induced liver injury: a population based case-control study. Br J Clin Pharmacol 2004;58(1):71–80 Avigan M. Drug-induced liver injury: Epidemiology and considerations of risk. American Thyroid Association, April 18, 2009. Available at: http://www.fda.gov/downloads/Drugs/NewsEvents/UCM164456.pdf. Accessed September 22, 2013 Behrman RE, Benner JS, Brown JS, McClellan M, Woodcock J, Platt R. Developing the Sentinel System—a national resource for evidence development. N Engl J Med 2011;364(6):498–499 Robb MA, Racoosin JA, Sherman RE, et al. The US Food and Drug Administration’s Sentinel Initiative: expanding the horizons of medical product safety. Pharmacoepidemiol Drug Saf 2012; 21(21, Suppl 1):9–11 Agarwal VK, McHutchison JG, Hoofnagle JH; Drug-Induced Liver Injury Network. Important elements for the diagnosis of druginduced liver injury. Clin Gastroenterol Hepatol 2010;8(5): 463–470 García-Cortés M, Stephens C, Lucena MI, Fernández-Castañer A, Andrade RJ; Spanish Group for the Study of Drug-Induced Liver Disease (Grupo de Estudio para las Hepatopatías Asociadas a Medicamentos GEHAM). Causality assessment methods in drug induced liver injury: strengths and weaknesses. J Hepatol 2011; 55(3):683–691 Bénichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol 1990;11(2):272–276 Danan G, Benichou C. Causality assessment of adverse reactions to drugs—I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol 1993;46(11):1323–1330 Rochon J, Protiva P, Seeff LB, et al; Drug-Induced Liver Injury Network (DILIN). Reliability of the Roussel Uclaf Causality Assessment Method for assessing causality in drug-induced liver injury. Hepatology 2008;48(4):1175–1183 Rockey DC, Seeff LB, Rochon J, et al; US Drug-Induced Liver Injury Network. Causality assessment in drug-induced liver injury using a structured expert opinion process: comparison to the RousselUclaf causality assessment method. Hepatology 2010;51(6): 2117–2126 Freston JW. Use and limitations of the RUCAM. AASLD-FDA Annual meeting on drug-induced liver injury, January 2006. Available at: http://www.fda.gov/downloads/Drugs/ScienceResearch/ResearchAreas/ucm079446.pdf. Accessed September 20, 2013 Maria VA, Victorino RM. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology 1997;26(3):664–669 Brinker AD, Wassel RT, Lyndly J, et al. Telithromycin-associated hepatotoxicity: Clinical spectrum and causality assessment of 42 cases. Hepatology 2009;49(1):250–257 Zapater P, Such J, Pérez-Mateo M, Horga JF. A new Poisson and Bayesian-based method to assign risk and causality in patients with suspected hepatic adverse drug reactions: a report of two new cases of ticlopidine-induced hepatotoxicity. Drug Saf 2002; 25(10):735–750 Lanctôt KL, Naranjo CA. Comparison of the Bayesian approach and a simple algorithm for assessment of adverse drug events. Clin Pharmacol Ther 1995;58(6):692–698 Théophile H, André M, Arimone Y, Haramburu F, MiremontSalamé G, Bégaud B. An updated method improved the assessment of adverse drug reaction in routine pharmacovigilance. J Clin Epidemiol 2012;65(10):1069–1077

56 57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

74

75

76

77

78

79

80

81 82

83

84

85

86

87

88

89

90

Seminars in Liver Disease

Vol. 34

No. 2/2014

225

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

DILI and Drug Development: A Regulatory Perspective

DILI and Drug Development: A Regulatory Perspective

Avigan

91 Liu Z, Shi Q, Ding D, Kelly R, Fang H, Tong W. Translating clinical

99 Urban TJ, Goldstein DB, Watkins PB. Genetic basis of susceptibility

findings into knowledge in drug safety evaluation—drug induced liver injury prediction system (DILIps). PLOS Comput Biol 2011; 7(12):e1002310 FDA Guidance for Industry. Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment. March 2005. Available at: http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126834.pdf. Accessed September 20, 2013 Reporting Serious Problems to FDA. . Available at: http://www. fda.gov/Safety/MedWatch/HowToReport/default.htm. Accessed September 20, 2013 LiverTox. Information on the diagnosis, cause, frequency, patterns, and management of liver injury attributable to prescription and nonprescription medications, herbals and dietary supplements. Available at: http://www.livertox.nih.gov/. Accessed September 23, 2013 FDA’s Sentinel Initiative – Ongoing Projects. 11 July 2012. Available at: http://www.fda.gov/Safety/FDAsSentinelInitiative/ucm203500. htm. Accessed September 20, 2013 Platt R, Carnahan RM, Brown JS, et al. The U.S. Food and Drug Administration’s Mini-Sentinel program: status and direction. Pharmacoepidemiol Drug Saf 2012;21(Suppl 1):1–8 Stang PE, Ryan PB, Racoosin JA, et al. Advancing the science for active surveillance: rationale and design for the Observational Medical Outcomes Partnership. Ann Intern Med 2010;153(9): 600–606 Lo Re V III, Haynes K, Goldberg D, et al. Validity of diagnostic codes to identify cases of severe acute liver injury in the US Food and Drug Administration’s Mini-Sentinel Distributed Database. Pharmacoepidemiol Drug Saf 2013;22(8):861–872

to drug-induced liver injury: what have we learned and where do we go from here? Pharmacogenomics 2012;13(7):735–738 FDA Guidance for Industry. Clinical pharmacogenomics: Premarketing evaluation in early phase clinical studies and recommendations for labeling. January 2013. Available at: http://www.fda. gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM337169.pdf. Accessed September 20, 2013 Watkins PB. Sharing information – asking questions: safety data warehouse? AASLD-FDA Annual Meeting on Drug-Induced Liver Injury, March 2012. Available at: http://www.aasld.org/dili/Documents/2012/3B-5_WatkinsN.pdf. Accessed September 20, 2013 Food and Drug Administration. Notice. Availability of masked and de-identified non-summary safety and efficacy data; request for comments. Fed Regist 2013 European Medicines Agency. Draft for public consultation. Publication and access to clinical-trial data. June 24, 2013. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2013/06/WC500144730.pdf. Accessed November 6, 2013 Mello MM, Francer JK, Wilenzick M, Teden P, Bierer BE, Barnes M. Preparing for responsible sharing of clinical trial data. N Engl J Med 2013;369(17):1651–1658 FDA Draft Guidance for Industry. Pharmacogenomic data submissions. March 2005. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079849.pdf. Accessed September 20, 2013 FDA Draft Guidance for Industry. Qualification process for drug development tools. October 2010. Available at: http://www.fda. gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM230597.pdf. Accessed September 20, 2013

92

93

94

95

96

97

98

Seminars in Liver Disease

Vol. 34

No. 2/2014

100

101

102

103

104

105

106

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

226

Copyright of Seminars in Liver Disease is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.