The reference standard should contain the same active ingredient as the test product under investigation. The reference standard should be the formulation that has the highest bioavailability for the same active ingredient.

The reference standard should be administered by the same route as the formulation under investigation.

The reference standard for a drug is usually a formulation currently approved and marketed which is well accepted by the medical profession and has a long history of clinical use. The reference standard is usually the innovator's or the original manufacturer's product.

In the crossover design, each subject receives all the products under investigation at different occasions. In this case, each subject will act as his/her own control. Time should be allowed between the administration of each product, to make sure that all the drug from the previous administration has been completely eliminated.

To design a study to compare the bioavailability of two different products A and B, subjects involved in the study are divided into two groups I and II. Group I receives product A and group II receives product B. After one week (or more, if complete drug elimination requires more than a week), group I should receive product B, and group II should receive product A. This way individual variation and variation due to sequence of drug administration can be eliminated.

- All ANDA requesting approval of a generic drug product.

- All supplemental applications filed for reporting changes in the manufacturing site, change in the manufacturing process, change in product formulation, change in dosage strength or products.

- There are data showing significant intra-batch and batch-to-batch variability in the bioavailability of the drug product.

- Drug products that do not meet any of the criteria that permit waiver of in vivo BE.

The in vivo bioequivalence requirements are waived by the FDA if the drug product meets one of the following criteria:

- Preparations intended for iv use or topical preparation intended for local effect.

- Oral dosage forms not intended for systemic absorption such as antacids and radiopaque media or products administered by inhalation as a gas or vapor.

- Oral solution, elixir, syrup, tincture, or other solubilized forms that contain a previously approved active ingredient and have no added inactive ingredient that is known to affect drug absorption.

- Drug products when the BE may be demonstrated by in vitro studies, such as fast release products of the BCS, Class I drugs (and class III drugs under certain conditions).