Alerts and Updates

FDA Releases Draft Guidance on Bioequivalence Requirements for ANDA Applicants

December 6, 2013

While FDA's newly issued draft guidance does not significantly change what an ANDA applicant must do to prove bioequivalence, it is important to review the draft guidance as it reflects FDA's current thinking.

On December 4, 2013, the U.S. Food and Drug Administration (FDA) issued a draft guidance on demonstrating bioequivalence for drugs submitted under an Abbreviated New Drug Application (ANDA). Entitled Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA, the new draft guidance does not significantly change the requirements for an ANDA applicant to prove bioequivalence. Comments on this draft guidance are due by March 5, 2014, to ensure consideration by FDA in the writing of the final version of the guidance. Because an ANDA applicant should be aware of FDA's current thinking on an issue as vital as bioequivalence, a few aspects of the draft guidance, which can be accessed here, are worth noting.

General considerations

The draft guidance is focused solely on demonstrating bioequivalence (BE) for ANDA products, and it specifically states that FDA will issue a separate guidance for products submitted under a New Drug Application (NDA), an NDA supplement or an Investigational New Drug application. It tracks closely FDA's March 2003 guidance titled Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations (the 2003 Guidance) and also incorporates information from other, related guidances into one document.

BE studies

The draft guidance provides additional information on the appropriate scenarios for using a nonreplicate crossover study, a single-dose parallel study or a replicate crossover study. For most dosage forms (both immediate release and modified release), the recommended study is the two-period, two-sequence, two-treatment, single-dose, nonreplicate crossover study. The guidance recommends single-dose, parallel studies where a crossover study may be impractical, such as for drugs with long half-lives. The replicate crossover study is the recommended alternative to the above studies for highly variable drugs. Further study considerations noted in the draft guidance include:

  • The recommendation to consider time-to-peak drug plasma concentration (Tmax) and specific indicators for area under the plasma concentration time curve (AUC) in single-dose and steady-state studies is outlined;
  • An optional pilot study to provide information can be useful in carrying out a pivotal bioequivalence study, including first point maximum plasma concentration determination;
  • Collection of blood samples at early time points of pivotal study is usually sufficient to assess peak drug concentration and should dissuade FDA from ignoring that data;
  • Single-dose studies are preferred, but steady-state studies are recommended when there are safety concerns with disrupting ongoing patient treatment; and
  • Fed BE studies are recommended for immediate-release products labeled to be taken only with food and modified-release products; recommended fed study criterion is the nonreplicate study with the "typical" FDA high-fat meal.

Establishing BE

Peak plasma concentration (Cmax) and AUC remain the key pharmacokinetic endpoints for demonstrating BE, which FDA defines as no significant difference between the rate and extent of drug absorption between the ANDA product and the reference listed drug when the products are administered at the same molar dose under similar conditions. For establishing BE, FDA recommends that the ANDA applicant provide the geometric means, arithmetic means, geometric mean ratios and 90-percent confidence intervals for AUC0-t, AUC0-inf and Cmax. FDA recommends that the applicant provides logarithmic transformation for the above measurements.

Special topics

The draft guidance continues to recommend measurement of only the parent drug and not its metabolite, but it slightly alters the recommendation for when to test for the metabolite. In the draft guidance, the primary metabolite is recommended for measurement if it is both "(1) formed substantially through presystemic metabolism (first-pass, gut wall, or gut lumen metabolism) and (2) [it] contribute[s] significantly to the safety and efficacy of the product."

The recommendations for measuring individual enantiomers are unchanged in the draft guidance. Specifically, the guidance recommends measuring individual enantiomers only when the enantiomers exhibit different pharmacodynamic and pharmacokinetic characteristics, when the primary efficacy and safety activity resides with the minor enantiomer and when nonlinear absorption is present for at least one of the enantiomers.

While not mentioned in the 2003 Guidance, the new draft guidance also recommends measuring endogenous compounds, which are compounds already present in the body because they are produced by the body or ingested. FDA recommends that the applicant measure and approximate the baseline endogenous levels in the blood and subtract those levels from the total concentrations measured after administration of the test drugs. The draft guidance provides different approaches for determining BE depending on whether the endogenous compound is produced by the body or is from dietary intake.


While FDA's newly issued draft guidance does not significantly change what an ANDA applicant must do to prove bioequivalence, it is important to review the draft guidance as it reflects FDA's current thinking. An ANDA applicant should also want to check—early in the development stage—whether a product-specific BE guidance covers any targeted product.

For Further Information

If you have any questions about this Alert or would like more information, please contact Kevin M. Nelson, any of the attorneys in our Intellectual Property: Generic Pharmaceuticals Practice Group or the attorney in the firm with whom you are regularly in contact.

Disclaimer: This Alert has been prepared and published for informational purposes only and is not offered, nor should be construed, as legal advice. For more information, please see the firm's full disclaimer.