Wednesday, September 8, 2010



As noted in CFR 320.24, several in vivo and in vitro methods can be used to measure product
quality bioavailability BA and to establish bioequivalence BE. In descending order of preference, these include pharmacokinetic, pharmacodynamic, clinical, and in vitro studies. These general approaches are discussed in the following sections of this guidance. Product quality bioavailability BA and bioequivalence BE frequently rely on pharmacokinetic measures such as AUC and Cmax that are reflective of systemic exposure.

                                                                                We will be going through following topics .
1.Pharmacokinetic Studies (will be discussed in separate post)

2.Pharmacodynamic Studies
3.Comparative Clinical Studies

4 In Vitro Studies (will be discussed in separate post)

2.Pharmacodynamic Studies

Pharmacodynamic studies are not recommended for orally administered drug products when the drug is absorbed into the systemic circulation and a pharmacokinetic approach can be used to assess systemic exposure and establish bioequivalence BE. However, in those instances where a pharmacokinetic approach is not possible, suitably validated pharmacodynamic methods can be used to demonstrate bioequivalence BE.

3. Comparative Clinical Studies

Where there are no other means, well-controlled clinical trials in humans can be useful to provide supportive evidence of bioavailability BA or bioequivalence BE. However, we recommend that the use of comparative clinical trials as an approach to demonstrate bioequivalence BE generally be considered insensitive and be avoided where possible (21 CFR 320.24). The use of BE studies with clinical trial endpoints can be appropriate to demonstrate BE for orally administered drug products when measurement of the active ingredients or active moieties in an accessible biological fluid (pharmacokinetic approach) or pharmacodynamic approach is infeasible.

A. Pharmacokinetic Studies

1. General Considerations

The statutory definitions of bioavailability BA and bioequivalence BE, expressed in terms of rate and extent of absorption of the active ingredient or moiety to the site of action, emphasize the use of pharmacokinetic measures in an accessible biological matrix such as blood, plasma,and/or serum to indicate release of the drug substance from the drug product into the systemic circulation , If serial measurements of the drug or its metabolites in plasma, serum, or blood cannot be accomplished, measurement of urinary excretion can be used to document bioequivalence BE.

This approach rests on an understanding that measuring the active moiety or ingredient at the site of action is generally not possible and, furthermore, that some relationship exists between the efficacy/safety and concentration of active moiety and/or its important metabolite or metabolites in the systemic circulation. To measure product quality bioavailability BA and establish BE, reliance on pharmacokinetic measurements may be viewed as a bioassay that assesses release of the drug substance from the drug product into the systemic circulation. A typical study is conducted as a crossover study. In this type of study, clearance, volume of distribution, and absorption, as determined by physiological variables (e.g. gastric emptying, motility, pH), are assumed to have less interoccasion variability compared to the variability arising from formulation performance. Therefore, differences between two products because of formulation factors can be determined.

2. Pilot Study
If the sponsor chooses, a pilot study in a small number of subjects can be carried out before proceeding with a full bioequivalence BE study. The study can be used to validate analytical methodology, assess variability, optimize sample collection time intervals, and provide other information. For example, for conventional immediate-release products, careful timing of initial samples may avoid a subsequent finding in a full-scale study that the first sample collection occurs after the plasma concentration peak. For modified-release products, a pilot study can help determine the sampling schedule to assess lag time and dose dumping. A pilot study that documents bioequivalence BE can be appropriate, provided its design and execution are suitable and a sufficient number of subjects (e.g., 12) have completed the study.


4. Study Designs

Nonreplicate crossover study designs are recommended for bioequivalence BE studies of immediaterelease and modified-release dosage forms. However, sponsors and/or applicants have the option of using replicate designs for bioequivalence BE studies for these drug products. Replicate study designs may offer several scientific advantages compared to nonreplicate designs.

The advantages of replicate study designs may be that they (1) allow comparisons of within-subject variances for the test and reference products, (2) provide more information about the intrinsic factors underlying formulation performance, and (3) reduce the number of subjects participating in the bioequivalence BE study. The recommended method of analysis of nonreplicate or replicate studies to establish bioequivalence BE is average bioequivalence,

5. Study Population

FDA recommend that, unless otherwise indicated by a specific guidance, subjects recruited for in vivo bioequivalence BE studies be 18 years of age or older and capable of giving informed consent. This guidance recommends that in vivo bioequivalence BE studies be conducted in individuals representative of the general population, taking into account age, sex, and race. FDA recommend that if the drug product is intended for use in both sexes, the sponsor attempt to include similar proportions of males and females in the study. If the drug product is to be used predominantly in the elderly, FDA also recommend that the sponsor attempt to include as many subjects of 60 years of age or older as possible. FDA recommend that the total number of subjects in the study provide adequate power for bioequivalence BE demonstration, but it is not expected that there will be sufficient power to draw conclusions for each subgroup. Statistical analysis of subgroups is not recommended. FDA recommend that restrictions on admission into the study generally be based solely on safety considerations. In some instances, it may be useful to admit patients into bioequivalencebioequivalence BE study. In accordance with CFR 320.31, for some products that will be submitted in ANDAs, an IND may be required for bioequivalence BE studies to ensure patient safety.

6. Single-Dose/Multiple-Dose Studies
Instances where multiple-dose studies can be useful are defined under CFR 320.27(a)(3). However, this guidance generally recommends single-dose pharmacokinetic studies for both immediate- and modified-release drug products to demonstrate bioequivalence BE because they are generally more sensitive in assessing release of the drug substance from the drug product into the systemic circulation FDA recommend that if a multiple-dose study design is important, appropriate dosage administration and sampling be carried out to document attainment of steady state.

7. Bioanalytical Methodology
FDA recommend sponsors ensure that bioanalytical methods for bioavailability BA and bioequivalence BE studies are accurate, precise, selective, sensitive, and reproducible. A separate FDA guidance entitled Bioanalytical Method Validation is available to assist sponsors in validating bioanalytical methods.

8. Pharmacokinetic Measures of Systemic Exposure
Both direct (e.g., rate constant, rate profile) and indirect (e.g., Cmax, Tmax, mean absorption time, mean residence time, Cmax normalized to AUC) pharmacokinetic measures are limited in their ability to assess rate of absorption. This guidance, therefore, recommends a change in focus from these direct or indirect measures of absorption rate to measures of systemic exposure. Cmax and AUC can continue to be used as measures for product quality bioavailability BA and bioequivalence BE, but more in terms of their capacity to assess exposure than their capacity to reflect rate and extent of absorption. FDA recommend that reliance on systemic exposure measures reflect comparable rate and extent of absorption, which in turn would achieve the underlying statutory and regulatory objective of ensuring comparable therapeutic effects. Exposure measures are defined relative to early, peak, and total portions of the plasma, serum, or blood concentration-time profile, as follows:

a. Early Exposure

For orally administered immediate-release drug products, bioequivalence BE can generally be demonstrated by measurements of peak and total exposure. An early exposure measure may be informative on the basis of appropriate clinical efficacy/safety trials and/or pharmacokinetic/pharmacodynamic studies that call for better control of drug absorption into the systemic circulation (e.g., to ensure rapid onset of an analgesic effect or to avoid an excessive hypotensive action of an antihypertensive). In this setting, FDA recommends use of partial AUC as an early exposure measure. FDA recommend that the partial area be truncated at the population median of Tmax values for the reference formulation. FDA also
recommend that at least two quantifiable samples be collected before the expected peak time to allow adequate estimation of the partial area.

b. Peak Exposure

FDA recommend that peak exposure be assessed by measuring the peak drug
concentration (Cmax) obtained directly from the data without interpolation.

c. Total Exposure
For single-dose studies, FDA recommend that the measurement of total exposure be:

* Area under the plasma/serum/blood concentration-time curve from time zero to time t (AUC0-t), where t is the last time point with measurable concentration for individual formulation.

* Area under the plasma/serum/blood concentration-time curve from time
zero to time infinity (AUC0-∞), where AUC0-∞ = AUC0-t + Ct/λz, Ct is the
last measurable drug concentration and λz is the terminal or elimination
rate constant calculated according to an appropriate method. FDA
recommend that the terminal half-life (t1/2) of the drug also be reported.

For steady-state studies, FDA recommend that the measurement of total exposure be the area under the plasma, serum, or blood concentration-time curve from time zero to time tau over a dosing interval at steady state (AUC0-tau), where tau is the length of the dosing interval.

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