Re: End of semester MCQ and short answer question

From: "Nick Holford" n.holford@auckland.ac.nz Subject: Re: [NMusers] End of semester MCQ and short answer question Date: Sun, July 17, 2005 11:34 am Thanks to those who took the test and responded to me. Not all responses were sent back to the open lists so I have anonymised all the responses. Question 1 ========== Extra marks were given to the PharmPK user who pointed out I should have used BLQ instead of LLQ. "I think what you meant to say in items 1(a) to (c) is "BLQ" (below the limit of quantitation) instead of "LLQ", since a value that is at the LLQ can just be reported as such as it is contained within the validated range." Quite correct! What I meant to ask would have been better expressed as follows. I have changed "LLQ" to "LLOQ" and use "quantification" (not "quantitation") for consistency with the FDA Bioanalytical guidance (see below). Q 1. LLOQ is the lower limit of quantification. Measured concentrations less than LLOQ are said to be below the limit of quantification (BLQ). Do regulatory Pharmacometric groups endorse? a. Ignoring BLQ values b. Imputing BLQ values as 0 c. Imputing BLQ values as 0.5*LLOQ d. Using the actual measurement i.e. ask the chemical analyst to tell the truth e. None of the above The most definitive material pertinent to Q1 came from the following quote from the Code of Federal Regulations. It was provided by a ex senior FDA person who would have dealt commonly with this kind of issue. This person and another current senior FDA person said they knew of no FDA guidance requiring the use of LLQ to modify data used for PK analysis. "Sec. 320.29 Analytical methods for an in vivo bioavailability or bioequivalence study. (a) The analytical method used in an in vivo bioavailability or bioequivalence study to measure the concentration of the active drug ingredient or therapeutic moiety, or its active metabolite(s), in body fluids or excretory products, or the method used to measure an acute pharmacological effect shall be demonstrated to be accurate and of sufficient sensitivity to measure, with appropriate precision, the actual concentration of the active drug ingredient or therapeutic moiety, or its active metabolite(s), achieved in the body." There is a 2001 Bioanalytical Method Validation guidance that defines LLOQ as concentrations with 20% CV ( http://www.fda.gov/cder/guidance/4252fnl.pdf). It says nothing that I can see about whether LLOQ should be applied when doing a PK analysis. Note that Bioanalytical Method validation statistics such as LLOQ are used to describe the properties of the assay. This guidance does not define how the concentrations are to be used. A subsequent 2003 Bioavailability and Bioequivalence document describes PK procedures but does not mention the use of LLOQ ( http://www.fda.gov/cder/guidance/5356fnl.pdf). There seems to be a common mis-perception that FDA requires the use of LLOQ in a PK analysis however no-one has provided any written evidence of this policy so far. My interpretation of these responses is that the closest answer to Q1 should be: "d. Using the actual measurement i.e. ask the chemical analyst to tell the truth" Question 2 ========== Almost full marks to the nmusers peson who gave a list of references of various opinions on dealing with BLQ values. Some credit was lost for using an obscure (Latex <grin>) character based formatting convention and providing a non-retrievable reference to recent work attributed to M. Tod. A prominent user of NONMEM responded: "The only advances have been I) my increasing conviction that whenever the pattern of BLQ values is consistent with the observed PK, that (a) [ignoring BLQ values], along with the adjustment described by Beal (2001) to account for the bias, is the way to go, and (II) the addition of a feature in NONMEM version VI that allows this sort of thing to be easily done." Nick