## Sunday, April 28, 2013

### Age Calculation in Clinical Trial Data Analysis with SAS Examples

In clinical trials, subject’s age is a critical demographic variable that needs to be collected. Age may be used in checking the inclusion/exclusion criteria, in sub-group analysis, in prognostic factor analysis, and so on. However, the Age variable is not directly collected on the case report form. Instead, the birth date is collected. Subject’s age will then need to be calculated based on the birth date and the date of screening visit. There are many ways in calculating the age and the results are slightly different. There seems to be no consensus in industry or CDISC indicating which method should be used. There was a paper discussing “How to Create Variables Related to Age”, some of the new functions were not included in the discussion.

Since we use SAS to analyze the clinical trial data, I listed the various ways to calculate the Age using SAS.

/*Macro AGE1 uses SAS INTCK function*/
%macro age1(from=,to=);
intck ('year', &from, &to) -
((month(&to) < month(&from)) or
((month(&to) = month(&from)) and (day(&to) < day(&from))));
%mend;

/*Macro AGE2 uses SAS INTCK function*/
%macro age2(from=,to=);
floor ((intck('month',&from,&to) - (day(&to) < day(&from))) / 12)
%mend age2;

data try;
input bdate date9. idate date9.;
age1=%age1(from=bdate,to=idate);
age2=%age2(from=bdate, to=idate);
age3=yrdif(bdate,idate, 'Age');       *This method uses SAS YRDIF function;
age365=(idate-bdate)/365;           *This method uses 365 as divider;
age36525=(idate-bdate)/365.25;  *This method uses 365.25 as divider;
age36525plus1=Floor(((idate-bdate)+1)/365.25);   *This method adds 1 and the divide by 365.25;
datalines;
01JAN12  31DEC12    /*this is one day short of one year*/
01JAN12  31DEC12    /*this is exactly one year*/
31DEC12  01JAN13    /*this is exactly one day, but cross the year*/
01JAN04  01JAN13    /*this is exactly nine years*/
01JUL12  01JAN13    /*this is 184 days*/
;
run;
proc print;
format bdate date9. idate date9.;
run;

 bdate idate age1 age2 age3 age365 age36525 age36525 plus1 01JAN2012 31DEC2012 0 0 1.00000 1.00000 0.99932 1 01JAN2012 01JAN2013 1 1 1.00000 1.00274 1.00205 1 31DEC2012 01JAN2013 0 0 0.00278 0.00274 0.00274 0 01JAN2004 01JAN2013 9 9 9.00000 9.00822 9.00205 9 01JUL2012 01JAN2013 0 0 0.50000 0.50411 0.50376 0

Based on the outputs, the calculation using YRDIF seems to be a good option. The use of YRDIF function is detailed in the SAS online document. The simple way using 365.25 as divider is actually a pretty good option. There is also an article in SAS blog discussing this. For an adult study, all of these approaches in calculating Age seem to be ok. However, for pediatric studies, different approaches could give quite bit different Age calculations.

On the regulatory side, there seems to be various ways in calculating the Age based on the documents submitted to FDA. In BLA 125145, Age in month was calculated as (1st vaccination date - Date of birth + 1) / (365.25/12). In SBA for EUFLEXXA approval, Age was calculated as: age = (date of informed consent - date of birth) / 365.25. In clinical review document for Actemra, the duration in study (in years) was calculated as:
Duration in study (years) = (date of last assessment – date of first TCZ dose +1) 365.25).

## Saturday, April 13, 2013

### Hy’s Law and Drug-Induced Liver Injury (DILI)

For clinical laboratory data analyses, statistical tabulations are typically generated to list the number of subjects in each treatment group with ALT, AST, TBL with n times of ULN (upper limit of normal (range)). For AST and ALT, n=3 and for TBL, n=2.

ALT, AST, TBL are all “liver enzymes” and are liver function test parameters. Other liver test parameters may also include GGTP and ALP, and others.
• ALT (alanine aminotransferase or SGPT)
• AST( aspartate transaminase or  SGOT)
• TBL (total bilirubin)
• GGTP (gamma-glutamyl transpeptidase)
• ALP (alkaline phosphatase)

In clincal trials, liver test parameters are the basis for assessing the so-called DILI (drug-induced liver injury).

Acording to FDA’s guidance “ Drug-Induced Liver Injury: Premarketing Clinical Evaluation“, when assessing the DILI, Hy’s law can be followed. Hy’s law is based on the work by Hy Zimmerman, a major scholar of drug-induced liver injury.
Hy’s Law cases have the following three components:
1.      The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control drug or placebo
2.      Among trial subjects showing such AT elevations, often with ATs much greater than 3xULN, one or more also show elevation of serum TBL to >2xULN, without initial findings of cholestasis (elevated serum ALP)
3.      No other reason can be found to explain the combination of increased AT and TBL, such as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of causing the observed injury
Finding one Hy’s Law case in the clinical trial database is worrisome; finding two is considered highly predictive that the drug has the potential to cause severe DILI when given to a larger population.

Hy’s law and DILI assessment is also specifically mentioned in FDA CDER Review Template “Clinical Safety Review of an NDA or BLA
At present, it appears that a potential for severe hepatotoxicity may be signaled by a set of findings sometimes called Hy’s Law, based on the observation by Hy Zimmerman, a major scholar of drug-induced liver injury (DILI), that a pure hepatocellular injury leading to jaundice had serious implications, a 10 to 50 percent mortality. Any Hy’s Law cases should be identified in the treatment group (e.g., subjects with any elevated aminotransferase (AT) of >3x upper limit of normal (ULN), alkaline phosphotase (ALP) >2xULN, and associated with an increase in bilirubin ≥2xULN).
My colleague used to argue with me about the use of 3 times x ULN for ALT and AST and cited the NCI’s CTC (common toxicity criteria) as the evidence. In NCI’s Common Toxicity Criteria, the 2.5 x ULN elevation of ALT and AST would be considered as adverse event with Grade 2 (corresponding to moderate AE severity). However, the NCI has shifted the Common Toxicity Criteria to CTCAE (Common Terminology Criteria for Adverse Events). In CTCAE, AST, ALT is consistent with the FDA guidance (i.e., 3xULN would be considered as grade 2)

to gauging drug induced liver injury by using individual patients’ baseline (instead of ULN) liver enzyme measurements, a move that some say could eliminate problems with the use of the upper limit of normal (ULN) and allow for the assessment of DILI in cases where there is underlying liver injury.