To receive approval for an Abbreviated New Drug Application (ANDA), an applicant must demonstrate, among other things, that the proposed drug product is bioequivalent to the Reference Listed Drug (RLD) or Reference Product.
This information is covered under FDA Guidance, “Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA.”
A generic drug is bioequivalent to the listed drug if the rate and extent of absorption of the drug do not show a significant difference from the rate and extent of absorption of the listed drug when administered at the same molar dose under similar experimental conditions. This can be achieved in either a single dose or in multiple doses.
For most products, the focus of bioequivalence (BE) studies is on the release of the drug substance from the drug product into the systemic circulation. During such BE studies, an applicant compares the systemic exposure profile of a test drug product to that of the RLD.
Five considerations to keep in mind for ANDAs
1. Appropriate Study Design
For highly variable drugs, a replicate crossover study may be an appropriate alternative to a parallel or nonreplicate crossover study and can be conducted as either a partial (three-way) or full (four-way) replication of treatment. In this design, one or both treatments should be administered to the same subject on two separate occasions. The replicate design has the advantage of using fewer subjects, although each subject should receive more treatments than in the two-treatment, crossover design.
2. Parent Drug Versus Metabolites
In general, applicants measure only the parent drug, rather than metabolites, because the concentration-time profile of the parent drug is more sensitive to changes in formulation performance than a metabolite, which is more reflective of metabolite formation, distribution and elimination. Primary metabolite(s), formed directly from the parent compound, should be measured if they are both: (1) formed substantially through presystemic metabolism and (2) contribute significantly to the safety and efficacy of the product. This approach should be used for all drug products, including pro-drugs. Applicants should analyze the parent drug measured in these BE studies using a confidence interval (CI) approach. Metabolite data can be used to provide supportive evidence of a comparable therapeutic outcome.
3. First Point Cmax
The first point of a concentration-time curve in a BE study, based on blood and/or plasma measurements, is sometimes the highest point, which raises questions of bias in the estimation of the maximum concentration observed (Cmax) because of insufficient early sampling times. A carefully conducted pilot study can enable an applicant to avoid this problem and properly characterize the Tmax. In the main BE study, collection of blood samples at an early time point, between five and 15 minutes after dosing, followed by additional sample collections (e.g., two to five) in the first hour after dosing is usually sufficient to assess peak drug concentrations. Failure to include early (5-15 minute) sampling times leading to first time-point Cmax values may result in the FDA not considering the data for affected subjects from the analysis.
4. Effects of Alcohol on Modified Release Drug Products
The consumption of alcoholic beverages can affect the release of a drug substance from a modified release (MR) formulation. The formulation can lose its modified release characteristics, leading to more rapid drug release and altered systemic exposure that can have deleterious effects on the drug’s safety and/or efficacy. The FDA recommends applicants developing certain extended release solid oral dosage forms to conduct in vitro studies to determine the potential for dose dumping in alcohol in vivo. If alcohol affects the in vitro profile, an in vivo BE study of the drug product when administered with alcohol may be required.
5. Endogenous Compounds
Endogenous compounds are drugs that are already present in the body either because the body produces them or they are present in the normal diet. Because these compounds are identical to the drug that is being administered, determining the amount of drug released from the dosage form and absorbed by each subject can be difficult.
Applicants should measure and approximate the baseline endogenous levels in blood (plasma), subtracting these levels from the total concentrations measured from each subject after the drug product has been administered. In this way, an estimate of the actual drug bioavailability from the drug product can be achieved.
Depending on whether the endogenous compound is naturally produced by the body or is present in the diet, the recommended approaches for determining BE differ as follows:
- When the body produces the compound, applicants should measure multiple baseline concentrations in the time period before administration of the study drug and subtract the baseline in an appropriate manner consistent with the pharmacokinetic properties of the drug.
- When there is dietary intake of the compound, intake should be strictly controlled both before and during the study. Subjects should be housed at a clinic before the study and served standardized meals containing an amount of the compound similar to that in the meals to be served on the pharmacokinetic sampling day.
For both of these approaches, applicants should determine baseline concentrations for each dosing period that are period specific. If a baseline correction results in a negative plasma concentration value, the value should be set equal to 0 before calculating the baseline-corrected area under the concentration-time curve (AUC). Pharmacokinetic and statistical analysis should be performed on both uncorrected and corrected data. Determination of BE should be based on the baseline-corrected data.
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