CFR 320Bioavailability and Bioequivalence Requirements

Historically, part 320 that addresses bioavailability (BA) and bioequivalence (BE) requirements was the outcome of a 1974 report that was prepared by the Drug Bioequivalence Study Panel that was convened under the U.S. Congress Office of Technology Assessment [5]. The charge to the panel was to "examine the relationships between chemical and therapeutic equivalence of drug products and to assess the capability of current technology—short of therapeutic trials in man—to determine whether drug products with the same physical and chemical composition produce comparable therapeutic effects." In the report one conclusion was that the standards and regulatory practices at the time did not insure bioequivalence for drug products. The report went on to make recommendations as to what could be done. As a result, in 1977 FDA finalized its Bioavailability and Bioequivalence Requirements via the FR which were subsequently codified in the CFR.

Although the impetus for the BA and BE requirements was for assuring therapeutic equivalence among duplicate or generic products, the requirements were also crafted to establish information needs to support the approval of NDAs for new molecular entities (NMEs) or new chemical entities (NCEs), as well as for defined changes for already approved NDA products. The inclusion of requirements for NDAs was to (i) foster better product quality, (ii) define or characterize what happens to a drug and its dosage form(s) when administered, (iii) provide information to help understand or interpret clinical safety and efficacy findings as appropriate, and (iv) provide useful information via the product's labeling or package insert for healthcare professionals.

Under Section 320.1, definitions are provided. The term bioavailability is defined as the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. It further states that for drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect that rate and extent to which the active ingredient or active moiety becomes available at the site of action. Other terms that are defined include bioequivalence, drug product, pharmaceutical equivalents, and pharmaceutical alternatives (see Glossary).

For part 320, key sections and subsections include the following, for which some are expanded upon as needed.

320.21 Requirements for submission of in vivo bioavailability and bioequivalence data.

Under this section, as related to NDAs, it indicates that "Any person submitting a full new application to the FDA shall include in the application either:

1. Evidence demonstrating the in vivo bioavailability of the drug product that is the subject of the application; or

2. Information to permit FDA to waive the submission of evidence demonstrating in vivo bioavailability."

This section goes on to indicate that any person submitting a supplemental application to FDA shall include in the supplemental application evidence demonstrating the in vivo bioavailability of the product or information to permit FDA to waive the submission of evidence demonstrating in vivo bioavailability for changes that include:

1. A change in the manufacturing process, including a change in product formulation or dosage strength, beyond the variations provided for in the approved application.

2. A change in the labeling to provide for a new indication for use of the drug product, if clinical studies are required to support the new indication for use.

3. A change in the labeling to provide for a new dosage regimen or for an additional dosage regimen for a special patient population, e.g., infants, if clinical studies are required to support the new or additional dosage regimen.

320.22 Criteria for waiver of evidence of in vivo bioavailability or bioequivalence.

320.23 Basis for demonstrating in vivo bioavailability or bioequivalence.

320.24 Types of evidence to establish bioavailability or bioequivalence.

This section covers the different types of in vivo and in vitro methods that can be used to determine bioavailability and bioequivalence. They are ranked in descending order of accuracy, sensitivity and reproducibility as stated or summarized as follows:

1. i. An in vivo test in humans in which the concentration of the active ingredient or active moiety, and, when appropriate, its active metabolite(s), in whole blood, plasma, serum, or other appropriate biological fluid is measured as a function of time, ii. An in vitro test that has been correlated with and is predictive of human bioavailability data; or iii. An in vivo test in animals that has been correlated with and is predictive of human bioavailability data.

2. An in vivo test in humans in which the urinary excretion of the active moiety, and, when appropriate, its active metabolite(s), are measured as a function of time.

3. An in vivo test in humans in which an appropriate acute pharmacological effect of the active moiety, and, when appropriate, its active metabolite(s), are measured as a function of time if such effect can be measured with sufficient accuracy, sensitivity, and reproducibility.

4. Well-controlled clinical trials in humans that establish the safety and effectiveness of the drug product, for purposes of establishing bioavailability, or appropriately designed comparative clinical trials, for purposes of establishing bioequivalence.

5. A currently available in vitro test acceptable to FDA (usually a dissolution rate test) that ensures human in vivo bioavailability.

6. Any other approach deemed adequate by FDA to establish bioavailability and bioequi valence.

• 320.25 Guidelines for the conduct of an in vivo bioavailability study.

Subheadings for the subsections under this section include:

a. Guiding principles.

b. Basic design.

c. Comparison to a reference material.

d. Previously unmarketed active drug ingredients or therapeutic moieties.

e. New formulations of active drug ingredients or therapeutic moieties approved for marketing.

f. Controlled release formulations.

g. Combination drug products.

h. Use of a placebo as the reference material.

i. Standards for test drug product and reference material.

Related to subsection (d) that addresses previously unmarketed active drug ingredients or therapeutic moieties, it states that the purpose of an in vivo bioavailability study is to determine the bioavailability of the formulation proposed for marketing as well as to determine essential pharmacokinetic characteristics of the active drug ingredient or therapeutic moiety such as rate of absorption, extent of absorption, half-life, excretion, metabolism, and dose proportionality. It further indicates that such characterization is a necessary part of the investigation of the drug to support drug labeling.

Under the umbrella to support drug labeling as outlined in this subsection, and with the experience that has been obtained over time since implementation of the BA and BE Requirements, along with advances in technology, updated and added information needs, in the realm of clinical pharmacology and biopharmaceutics (as defined above and under the purview of 21 CFR 320), are being asked to be addressed by sponsors in their drug development programs for new products. As will be covered in the section that discusses FDA guidances, FDA provides more current thinking on such information needs as related to the different aspects of clinical pharmacology and biopharmaceutics. (Note: Likewise in ICH guidelines, they too present and expand upon information needs in the areas of clinical pharmacology and biopharmaceutics for drug product registration, most of which is consistent with FDA guidances.)

• 320.26 Guidelines on the design of a single-dose in vivo bioavailability study.

• 320.27 Guidelines on the design of a multiple-dose in vivo bioavailability study.

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