FDA Bioequivalence Guidance Expands Crossover Designs For ANDA Studies
Executive Summary
Guidance “will be especially useful” for planning studies to support postapproval ANDA changes, the agency notes.
FDA released the ANDA portion of revised guidance on bioequivalence testing Dec. 5, giving generic sponsors a few more pre-approved study designs options.
Topics addressed in the draft Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA previously were covered as part of separate guidances on studies for NDAs and INDs, as well as ANDAs, to determine the bioequivalence of oral drugs, and on the effects of food on bioequivalence.
A separate guidance on bioavailability for NDAs, NDA supplements and INDs will be issued shortly, the agency says, noting that “separation of the guidances according to application type will be beneficial to applicants.”
The draft ANDA guidance, which is intended for use in conjunction with product-specific bioequivalence guidance, applies to dosage forms intended for oral administration, and for non-orally administered drugs, such as transdermal patches and some rectal and nasal products, when those drugs’ bioequivalence can be ascertained by systemic exposure measures.
The guidance also “will be especially useful” for planning studies to support post-approval ANDA changes, the agency notes.
As with the joint guidance, Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations, pharmacokinetic studies are the preferred method for assessing bioequivalence for generic products, followed in descending preference by pharmacodynamics, clinical and in vitro studies.
FDA explained in a Federal Register notice that changes from the earlier guidances are based on experience with them and scientific information that has become available since their issuance. Officials from the Office of Generic Drugs reported in 2012 that generic drug sponsors increasingly are using novel and science-based approaches to assess bioequivalence (Also see "FDA Approving More ANDAs That Use Novel Bioequivalence Methods" - Pink Sheet, 25 Oct, 2012.).
The joint guidance recommends non-replicate crossover study designs for immediate-release and modified-release dosage forms, offering replicate designs as an option.
The ANDA draft adds a single-dose parallel design to the mix and gives some more information on the desired designs. For crossover studies, the agency recommends a two-period, two-sequence, two-treatment, single-dose in healthy subjects. Each participant should receive both the test product and the reference drug, the agency says.
For drugs with pharmacokinetic half-lives longer than 24 hours, the guidance says a single-dose, parallel design can be utilized, with each treatment administered to a separate group of subjects with similar demographics.
Replicate Crossover Studies
The draft guidance says a replicate crossover study may be an appropriate alternative to the first two types of trials and can be either a partial (three-way) or full (four-way) replication of treatment. It “is especially useful for highly variable drugs,” which are those with an intra-subject variability of ≥30%.
FDA received support for this option for highly variable drugs from an April 2012 advisory panel (Also see "FDA Reverses Stance On Bioequivalence Standards For Mesalamine" - Pink Sheet, 30 Aug, 2010.).
Each participant in a replicate crossover study should receive one or both treatments on two separate occasions, FDA says. The advantage of the replicate design is it involves fewer participants, the agency notes, “although each subject should receive more treatments than in the two-treatment, crossover design.”
Alternatively, a single-dose, randomized, three-period reference-scale average bioequivalence study is appropriate, FDA says. This approach adjusts the bioequivalence limits of highly variable drugs by scaling to the within-subject variability of the reference product and imposing a 0.8 to 1.25 limit on the geometric mean ratio. Within-subject variability is assessed using a three-way modified replicate-design study in which the reference product is given twice and the test product once.
If sponsors want to use alternative designs or analysis methods, such as a sequential design or the scaled-average bioequivalence, FDA recommends submitting a complete protocol to the agency for review and comment joint to study initiation.
Time-To-Peak Concentration Informative
Both the joint guidance and the ANDA document recommend measuring peak drug concentration (Cmax) obtained directly from the data, without interpolation, but the latter also notes that time-to-peak drug plasma concentrations (Tmax) can “provide important information regarding the rate of absorption.”
Tmax has been an area of focus for FDA regarding extended-release drugs (Also see "Generics May Have Tmax Flexibility, FDA Says" - Pink Sheet, 2 May, 2013.).
For orally administered immediate-release drugs, the draft guidance notes that peak and total exposure generally demonstrate bioequivalence. As an early exposure measure, partial area under the curve (AUC) sometimes can be used. The draft ANDA guidance notes that the time to truncate the partial area should be related to a clinically relevant pharmacodynamics measure and recommends that “sufficient quantifiable samples” be used to allow an adequate estimate of the partial area. The joint guidance recommends truncation at the population median of Tmax values for the reference formulation and that at least two quantifiable samples be collected.
The draft ANDA guidance recommends single-dose, two-period, two-treatment, two-sequence, crossover studies to assess fed bioequivalence. Like the Food-Effect Bioavailability and Fed Bioequivalence Studies guidance, the draft ANDA guidance calls for a fed study when a fasting in vivo bioequivalence study is recommended for orally administered, immediate-release drugs, except when reference product labeling says the product should be taken only on an empty stomach. It does not include the exception in the other document for rapidly dissolving products where the generic and reference have similar dissolution profiles and contain a drug substance with high solubility and high permeability.