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 will be 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.

- Evidence that different drug products do not give comparable therapeutic effects.

- Evidence that the drug products exhibit very narrow therapeutic range and safe and effective use of the drug require dosage titration and patient monitoring.

- Factors related to the physicochemical properties of the drug such as low water solubility, slow dissolution rate, particle size and surface area of the active drug ingredient is critical in its absorption, certain structure forms of the active drug ingredient is critical in its dissolution and absorption, drug products with high ratio of excipients to active ingredient, and if a specific additive can affect the absorption of the active ingredient.

- Evidence of poor overall absorption (< 50% of dose), significant intestinal metabolism, rapid elimination of the drug after absorption, degradation in a specific GIT region, and if the drug follows dose-dependent pharmacokinetics.

The in vivo bioavailability 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.