Docket Management
Docket: 01D-0488 - Draft Guidance - Food-effect Bioavail and Fed Bioequiv Studies
Comment Number: EC -4

Accepted - Volume 1

Comment Record
Commentor Ms. Juan He Date/Time 2002-01-28 14:29:19
Organization Biovail Contract Research Organization
Category Company

Comments for FDA General
1. General Comments 1. Page 2, Line 45 – 49 BA and BE comparison: “It proposes an equivalence limit of 80 – 125% for the analysis of Cmax and AUC data 90% confidence interval (CI) in food-effect BA studies as evidence of an absence of food effects and in fed BE studies to demonstrate the BE of a test and reference product.” Comments: AUC data can estimate the systemic exposure of the drug to human body, and generally, two formulations whose rate and extent of absorption differ by 20% or less are considered bioequivalent. The Cmax parameter provides an indication that the drug is systemically absorbed to sufficiently provide a therapeutic response and in addition, it provides a warning of potentially toxic levels of the drug. Therefore, unlike the AUC, the Cmax term is an indirect PK parameter to define the rate and extent of the absorption of a drug. In this context, the point estimate of the Cmax comparison of the test to the reference should be sufficient to provide the difference or likelihood of the two formulations. 2. Page 7, Line 266: Tlag: Please define the Tlag. Please advise what definition of Tlag should be used for the FDA’s BA and BE studies. Comments: most textbooks state: “The time delay prior to the commencement of first-order drug absorption is known as the Lag time”. However, some individuals have been using the time corresponding to the first measurable concentration as the lag time with the rational that it’s difficult to obtain the real time point with the zero concentration, and furthermore, it depends on the sampling schedules. A more accurate way is to plot the two residual lines obtained from the absorption profile, and the time at the point of intersection on the x-axis is the lag time. This approach is mainly used in academia and by some innovators in the early stages for the full characterization of the compounds. It would not be necessary for the BA and BE studies. 3. Page 9, Line 318: “Tmax values for the test and reference products are expected to be comparable based on clinical relevance” Comments: what is the criterion for this Tmax comparison? What is the definition of the term “comparable”? How to achieve it? The ANDA studies don’t usually have clinical endpoints so how can we connect the clinical significance to the Tmax, based on the literature’s or innovator’s information? Should the Tmax evaluation be mainly focused on the drugs with clinically relevant claims for fast release/action or the claim(s) of signs associated with adverse effects? or for information purpose only? 4. Page 9, Line 351-352: “Different beverages…” Comments: can the FDA provide a list of the beverages recommended for testing? There should be some constraints placed on this criteria otherwise an Innovator could frivolously associate their drug with many variations of the same beverage.

EC -4