evaluation may be important in several circumstances, as dis-cussed in the sections below.
BE documentation may be useful during the IND-NDAperiod to establish links between: (i) early and late clinicaltrial formulations; (ii) formulations used in clinical studiesand stability studies, if different; and (iii) clinical trial formu-lations and the to-be-marketed drug product. In each com-parison, the new formulation or new method of manufactureis the test product, and the prior formulation or method of manufacture is the reference product. It may not be possibleto conclude BE because the test product produces higher orlower measures of rate and extent of absorption or becausethe performance of the test or reference is more variable. Insome cases,
is observed because of inad-equate numbers of subjects entered into the BE study.
Sponsors of ANDAs are required to establish BE be-tween a pharmaceutically equivalent generic drug productand the corresponding listed drug.
Information on the types of
BE studies and
dissolution needed for postapproval changes to drugproducts approved as either NDAs or ANDAs are providedin FDA guidances. In the presence of certain major changesin components and composition, and/or method of manufac-ture after approval,
BE between pre- and postchangeproduct may need to be reestablished. Under such circum-stances, for approved NDAs, the drug product after changeshould be compared with the drug product before change,whereas for approved ANDAs, the drug product after changeshould be compared with the reference listed drug.
THE SECOND QUESTION: TEST PROCEDURES
The second question focuses on the test procedures thatare considered adequate to address the primary BA and BEquestion. Several
methods are appropriateto document BA and BE. In descending order of preference,the US regulations include pharmacokinetic, pharmacody-namic, clinical, and
studies (4). Willingness to rely ontest procedures other than clinical studies is based on theassumption that pharmacokinetic and pharmacodynamic ap-proaches and/or
approaches, along with appropriategoalposts, adequately reflect clinical safety and efficacy out-comes.
The statutory definition of BA and BE, expressed in rateand extent of absorption of the active moiety or ingredient tothe site of action, emphasizes the use of pharmacokineticmeasures to indicate release of the drug substance from thedrug product with absorption into the systemic circulation.This approach rests on an understanding that measurement of the active moiety or ingredient at the site(s) of action is gen-erally not possible and that some predetermined relationshipexists between the drug concentration at the site of actionrelative to that in the systemic circulation. A typical BE studyis conducted as a crossover study, in which clearance andphysiologic variables (
gastric emptying, motility, and pH)are assumed to have less interoccasion variability within anindividual compared with variability between individuals.Where needed, a pilot study may be useful to validate analyticmethodology, to assess intra- and intersubject variability insystemic exposure measures, and to optimize sample collec-tion times. Although some authors have stated that multiple-dose studies are useful in establishing BA and BE (10), single-dose studies to document BE may be preferred because theyare generally more sensitive in assessing
release of thedrug substance from the drug product (11
13).A goal in BA and BE studies is to assess rate and extentof drug absorption. Extent of absorption is readily measuredby AUC either to the last sampled time point (AUC
) orfollowing extrapolation to time infinity (AUC
). Measure-ment of the true rate of absorption is difficult, given that ratevaries continuously over time (14,15). A recent FDA guid-ance, therefore, has recommended that measures of systemicexposure be used to reflect clinically important differencesbetween test and reference products in BA and BE studies(16). These measures include (i) total exposure (AUC
for single-dose studies and AUC
for steady-statestudies), (ii) peak exposure (Cmax), and (iii) early exposure(partial AUC to peak time of the reference product for animmediate-release drug product). Reliance on systemic expo-sure measures will reflect comparable rate and extent of ab-sorption, which in turn, will achieve the underlying goal of assuring comparable therapeutic effects.
Pharmacologic Effect (Pharmacodynamic) Studies
Locally acting drug products include oral inhalation drugproducts, such as metered dose inhalers and dry powder in-halers, and topically applied dermatologic drug products suchas creams and ointments. These drug products deliver an ac-tive moiety or active ingredient to local sites of action wherethey exert their primary clinical effects. Pharmacokineticstudies measure systemic exposure but are generally inappro-priate to document local delivery BA and BE. In such cases,BA may be measured, and BE may be established, based ona pharmacodynamic (PD) study, providing an appropriate PDendpoint is available, which can be studied with sufficientaccuracy, sensitivity, and reproducibility. Bronchodilatordrug products, such as albuterol metered dose inhalers, pro-duce relaxation of airway smooth muscle. For these drugproducts, a PD endpoint, based either on increase in forcedexpiratory volume in 1 s (FEV
) or on measurement of PD
(the dose or concentration, respectively, of a chal-lenge agent) (17,18), is clinically relevant and may be used forBA and BE studies.An essential component of a BA or BE study based on aPD response is documentation of a dose-response relation-ship. The dose-response curve should be characterized as partof the study. In the absence of other evidence, the commonlyused Emax model is assumed as the default model. To estab-lish BE, the study is conducted in the sensitive region of thedose-response curve (19). A BE study conducted near theplateau of response will be insensitive to differences in drugdelivery between the test and reference products and will,thus, require increased numbers of subjects to detect product
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