x B versus x ULN for Assessing Drug Effects

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1 x B versus x ULN for Assessing Drug Effects Leonard B. Seeff, M.D. The Hill Group and the U.S. Food and Drug Administration Detecting and Evaluating Drug-Induced Liver Injury and Dysfunction University of Maryland, March 20,

2 Background Drug-induced liver injury (dili) is among the most common reasons for a drug in development not coming to market Clinical trials are conducted to assess drug efficacy but are required also to monitor for adverse events that includes repeated ALT testing for potential dili Clinical trials of new drugs are commonly performed in multiple different countries

3 Background Screening for potential dili commonly involves different laboratories in different countries, each of which may use a different ULN for ALT and thus the ULN is often set arbitrarily at a normalized 40 U/L, regardless of age, gender, or race To introduce consistency, a single central laboratory is commonly utilized but may delay reporting of results

4 Drug-Induced Liver Injury Drug-induced liver injury (dili) can present as hepatocellular, cholestatic or mixed injury most easily defined through use of the R value* Since there is no specific biomarker for detecting dili, the accepted first signal for its possible diagnosis is an increase in the ALT value for hepatocellular injury and an increase in the ALP value for cholestatic injury, both temporally associated with receipt of a drug *R = ALT/ALT ULN ALP/ALP ULN Hepatocellular >5; cholestatic <2; mixed 2<R<5

5 Diagnosing Drug-Induced Liver Injury The impact of the identified increase depends on its level relative to the baseline value obtained just before or at the start of drug treatment Currently there is uncertainty about the level of ALT increase that should be considered a signal of importance for possible impending dili Although any increased value may be meaningful, a level of 3 x or 5 x the baseline level for ALT and of 2 x the baseline level for ALP is generally regarded a change of concern warranting action

6 Baseline Value Traditionally, the baseline value used for comparison is the upper limit of normal (ULN) for that test, in this case, the ALT The ULN is generally set for each laboratory by screening a large local population believed to be healthy and then selecting as a reference number the mean value +2 standard deviations (95 th percentile)

7 Upper Limit of Normal While 40 U/L for the ALT is commonly used as the ULN, it is clearly not a universal measure of normality Wide variations are found in the calculated ULN for the ALT among laboratories depending upon the population screened for this purpose* Variations result from such factors as age, gender, race, the presence of such metabolic features as BMI, glucose, cholesterol, triglycerides, etc., and unrecognized chronic hepatitis, mostly hepatitis C Neuschwander-Tetri et al, Arch Intern Med 2008; Dutta A et al, Hepatology 2009; Cai Z et al, Eur J Clin Pharmacol 2009

8 Upper Limit of Normal What is referred to as the ULN is, however, not necessarily indicative of normal health Prati et al were the first to report that the ULN for ALT was far lower than the 40 U/L suggested by manufacturers of tests and that there was a distinct difference by gender Multiple additional surveys since then involving differing populations from various countries support these observations and while the values are almost always lower than 40 U/L, they differ by survey

9 Surveys of Different Populations for Upper Limit of Normal (ULN) for ALT European & American Surveys Author Year ALT Level U/L Population Studied Piton 1988 M 42; F 31 Blood donors Prati 2002 M 30; F 19 Blood donors Kariv 2006 M 44; F 32 Population-based Prati 2006 M 25; F 22 Treatment trials Vd Poorten Juvenile offenders Ruhl 2012 M 24; F 18 NHANES Piton, Hepatology, 1998; Prati, Ann Intern Med 2002; Kariv. Liv Int 2006 Prati, J Hepatol, 2006; Van der Poorten, Hepatology 2007; Ruhl, Hepatology 2012

10 Surveys of Different Populations for Upper Limit of Normal (ULN) for ALT Asian Surveys Author Year ALT Level U/L Population Studied Lee 2010 M 35; F 26 Liver donors, Korea Kang 2011 M 31; F 23 Health survey, Korea Sohn 2012 M 34; F 24 Blood donors, Korea Park 2012 M 34; F 25 Health survey, Korea Wu 2012 M 21; F 17 Health survey, Taiwan Zhang 2012 M 35; F 23 Han population, China Lee JK, Hepatology 2010; Kang HS, J Gastroenterol Hepatol 2011; Sohn W, J Gastroenterol Hepatol 2012; Park SH Clin Biochem 2013; Wu W-C, Aliment Pharmacol Therap 2012; Zheng M-H PloS 2012

11 Impact of ALT Levels There is no specific level of the ULN for ALT that is universally accepted as the norm Data suggest that the higher the start ALT level, the more likely the development/progression of dili Liver disease progression has been reported even among persons with high normal ALT levels (i.e,. 20 to 40 U/L)* *Kim HC, BMJ 2004; Kunde SS, Hepatology 2005; Van der Poorten D. Hepatology 2007; Piton A, Hepatology 1998; Suh S-Y, Metabolism 2009; Lee JK, Hepatology 2010; Kang HS, Gastroenterolgy 2011

12 Kim H, et al. BMJ 2004

13 Kim H, et al. BMJ 2004

14 Impact of ALT Levels On Cardiovascular Disease All cause and cardiovascular disease mortality has been found to be higher in those with higher ALT values, even those with high normal levels Dhamendrakumar AP, Metabolism 2007; Goessling W.,Gastroenterology 2008; Schindhelm RK, Atherosclerosis 2007; Yun KE, Atherosclerosis 2009

15 Thus There is a lack of consistency from laboratory to laboratory of the locally established ULN of ALT The frequently utilized ULN for ALT of 40 U/L as commonly suggested by the manufacturer does not necessarily establish a normal or healthy cut-off level What a universally-acceptable ULN for the ALT should be has not been established but is clearly far less than 40 U/L and differs by gender

16 Question Given the complexities of the ULN for ALT, is the use of the ULN the best measurement against which to determine the possibility of potentially developing hepatotoxicity?

17 Reasons to Consider an Alternative Approach to Monitoring for DILI Because possible developing dili is: - currently based on comparing an unexplained increased ALT level during treatment with the laboratory ULN at baseline - values for the ULN commonly vary widely among different laboratories - there is no universally-accepted ULN of the ALT - the healthy value is clearly lower than the frequently used level of 40 U/L, An alternative approach to comparison should be considered

18 Alternative Comparator We propose that the preferable baseline comparator should be the individual patient s own ALT level measured prior to and at the time of starting drug treatment A subsequent rise during treatment would then reflect a more meaningful increase for that individual person measured against their own baseline rather than an arbitrary pre-set value, and avoids the gender difference

19 Measuring Baseline Abnormal ALT Value Measuring a single baseline value may not, however, reflect a stable ALT environment for that patient, and thus the ALT should be measured on at least two occasions separated by at least 2-4 weeks before enrolling the patient into the trial; three measurements would be preferable but may not be practical. If the two values vary little or show a decline, the patient would be eligible for the trial, all else being equal

20 Measuring Baseline Abnormal ALT Values If the ALT value(s) increases beyond a given degree, say 30%, the patient may be developing important liver disease that might preclude enrollment in the trial A simple way to assess the extent and importance of the increase is to utilize the equation developed by Dr. John Senior If the increase is determined to be of concern, the patient should not be enrolled or enrollment should be delayed until the liver tests resolve

21 Conclusion We therefore propose that instead of, or in addition to, the utilization of the individual laboratory s ULN as the baseline value when embarking on a clinical trial, it should be the confirmed ALT value of the study patient him/herself at baseline that should be used This avoids the problem of the variability of the ULN of ALT from laboratory to laboratory, the variability by gender, age and race, and, as will be discussed, the issue of pre-existing liver disease Cai Z, Eur J Clin Pharmacol 2009

22 Calculate BASELINE from Screening & Pretreatment Values an Excel program, bslcalc.xls Take ALT as an example, tests 3 weeks apart Use both screening and pre-treatment results (do not start treatment until results of pre-treatment test results known) (if slope of ALT value rises at >30% per month, best not to start experimental drug or controlled study, but investigate for probable Cause of rising values) Screening date 29-Jan-13 value, U/L 32 Pre-treat date 17-Feb-13 value, U/L 36 slope PROCEED baseline 34 average of 2