The FDA has published several guidelines concerning testing the bioavailability of drugs since 1987. Three documents together present the FDA’s current thinking on everything related to bioavailability and bioequivalence.
We present the main points from these three documents relevant for NDAs (New Drug Applications) and ANDAs (Abbreviated New Drug Applications).
The Key Purpose of NDA Documentation
The FDA emphasizes that the documentation accompanying any NDA should recapture the entire story of the drug for the FDA. The documentation should help the FDA reach a decision on the following:
- The safety and efficacy of the drug for its proposed therapeutic use, including how the benefits of the new therapeutic outweigh the associated risks
- The appropriateness of the proposed labeling, including what the package insert should contain
- The adequacy of the methods used in the drug manufacturing process, along with the controls used to preserve the drug’s identity, quality, purity, and strength.
FDA Guidance for Bioavailability and Bioequivalence Studies Submitted in NDAs
The purpose of this document is to guide the pharmaceutical industry on bioavailability and bioequivalence information requirements to comply with the 21 CFR part 320. It relates mainly to dosage forms for oral administration.
However, if reliance on systemic exposure measures is appropriate for document bioavailability and bioequivalence definition, these guidelines may also apply to specific non-oral doses.
Bioavailability Studies and Bioequivalence Studies
The guidance document recommends the following bioavailability studies and bioequivalence studies in descending order of preference:
- Pharmacokinetic Studies
- Pharmacodynamic Studies
- Comparative Clinical Studies
- In Vitro Studies
General Guidelines for Designing Studies and Handling Data
- A bioavailability study or a bioequivalence analysis needs to be conducted after an overnight fast of at least 10 hours.
- There is a separate guideline for testing the bioavailability of drugs with food-effect and fed bioequivalence studies.
- Both the test and the reference products need to be administered to an appropriate number of subjects in combination with 8 ounces, i.e., 240 ml of water.
- For an appropriate test of the bioavailability of drugs, the highest marketed strength needs to be administered as a single dose.
- An adequate washout period should set apart each treatment. For instance, measuring >5 half-lives of the moieties.
- The difference between the assayed drug content of the test product batch and the reference product should not be more than +/-5 percent.
- Samples of the test and reference products need to be maintained for at least 5 years.
- Test subjects should:
- Have as much water as desired except one our before and after test drug administration
- Given standard food after a minimum of 4 hours post administering the test drug
- Should not consume alcohol at least 24 hours before each study period and until the last sample has been collected.
- The recommended medium for sampling is blood. The recommended range of samples is 12-18, including a pre-dose sample.
- The sampling needs to continue for a minimum of three half-lives of the drug.
- The FDA recommends that applicants do not round off confidence interval values.
Recommendations for ANDAs
For ANDAs, the FDA, in its 2013 guidelines, recommends the submission of bioequivalence studies with pharmacokinetic endpoints. This document provides general guidelines for both fed and unfed bioequivalence studies for ANDAs.
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The document also provides detailed parameters for the following:
- Pharmacokinetic information necessary for a submission
- Statistical information details necessary for a submission
- Not rounding off the confidence interval value.