LCMS Based “BABE” Studies in the Pharma Industry

• Two drug products are considered pharmaceutical equivalents if they contain identical amounts of the same active ingredient.
• Two drugs are identified as pharmaceutical alternatives to each other if both contain an identical therapeutic moiety, but not necessarily in the same amount or dosage form or as the same salt or ester.
• Two drug products are said to be bioequivalent if they are pharmaceutical equivalents (i.e., similar dosage forms made) or pharmaceutical alternatives (i.e., different dosage forms) and if their rates and extents of absorption do not show a significant difference to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives become available at the site of action when administered at the same molar dose under similar conditions in an appropriately designed study.

Bioequivalence assessment is considered as a surrogate for clinical evaluation of the therapeutic equivalence of drug products. A typical process for bioequivalence assessment is to conduct a bioequivalence study with male healthy volunteers under the assumption that bioequivalence (relative bioavailability) of the drug product under investigation is predictive of clinical outcomes (i.e., safety and efficacy) of the drug product in clinical trials. A bioequivalence study is often conducted utilizing a crossover design that allows comparison within individual subjects, i.e., each subject is at his/her own control. On the basis of the pharmacokinetic (PK) data collected, bioequivalence can then be assessed using valid statistical methods according to some pre-specified regulatory criteria for bioequivalence. As indicated by the FDA, an approved generic drug product can be used as a substitute for the brand-name drug. The assumption that relative bioavailability is predictive of clinical outcomes, criteria for bioequivalence, basic considerations for conduct of a bioequivalence study such as study design, sample size, and statistical methods, current issues including one-size-fits-all criterion and drug interchangeability, and recent development such as bioequivalence assessment for highly variable drugs (HVDs) should be carefully studied and considered during the process of effective drug development.

Objectives of Bioavailability

1. Bioavailability data provide an estimation of the fraction of the drug absorption, distribution, metabolism, excretion, and the effects of food on the absorption of the drug, dose proportionality, or linearity in the pharmacokinetics of the active moieties and when appropriate inactive moieties.
2. BA provides useful information to establish dosage regimens and to support drug labelling, such as distribution and elimination characteristics of the drug.
3. Bioavailability of drug product aids in the FDA’s evaluation of the safety and effectiveness of a product in an IND, NDA, or NDA supplements.
4. The Bioavailability of formulations used in drug development may be needed to compare:

• The early and late clinical trial formulations
• The formulations used in clinical trials and stability studies, if different
• The clinical trial formulations and to-be-marketed drug products, if different
• The equivalence of product strengths; and
• The comparison of two different products that are the subject of a new drug application (NDA) submission.

Objectives of Bioequivalence

1. To measure and compare formulation performance between two or more drug products.
2. Bioequivalence provides a link between the pivotal and early clinical trial formulation.
3. To determine the therapeutic equivalence between the pharmaceutical equivalence generic drug product and a corresponding reference listed drug.
4. For an innovator drug product, bioequivalence studies establish the performance of the new formulation product intended for marketing with already approved innovator drug product to evaluate safety/efficacy of new formulation drug product. Efficacy vs Potency.
5. To provide information on product quality and performance when there are changes in components, composition, and method of manufacture after approval of the drug product.