Under the Federal Food, Drug and Cosmetic Act (FD&C Act, Section 505(j)), generic drug applications must be essentially identical to the drug which they reference, also known as the reference-listed drug (RLD). They must, for example, have the same active ingredient, and may only differ slightly in their excipients. Any substantial changes, such as a change to the route of administration, must be approved by FDA through a suitability petition. Section 505(j)(2)(iv) outlines the basic requirements for conducting bioequivalence studies, and requires “information to show that the new drug is bioequivalent to the listed drug”—except in cases of a suitability petition—as well as information showing the drug to be of the same pharmacological or therapeutic class, and that it will have the same “therapeutic effect” as the RLD.
To assist manufacturers, FDA has published more than 1,100 guidance documents to help companies generate the data that will satisfy FDA’s data requirements for specific products. For example, if a company wants to manufacture a generic transdermal extended release nicotine patch, it can find a guidance document recommending it conduct a skin irritation and sensitization study, as well as a bioequivalence study with pharmacokinetic endpoints.
Updated Guidance on BE Testing
But how would a company go about conducting that bioequivalence (henceforth ”BE”) study with pharmacokinetic endpoints? FDA has an answer for inquiring minds. On 4 December 2013, FDA published new draft guidance, Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA, that “revises and replaces” two earlier guidance documents on that topic, offering up new advice.
“The guidance is generally applicable to dosage forms intended for oral administration and to non-orally administered drug products in which reliance on systemic exposure measures is suitable for documenting BE (e.g., transdermal delivery systems and certain rectal and nasal drug products),” FDA explains in the guidance. “We believe that the guidance will also be useful when planning BE studies intended to be conducted during the postapproval period for certain changes in an ANDA.”
The extensive 24-page guidance offers up advice on a range of factors to consider when conducting BE testing. For example, FDA gives advice on general considerations, pilot studies, pivotal BE studies, study designs, the study population, single-dose studies, steady-state studies, bioanalytical methodologies, measures of rate and extent of exposure, fed BE studies, sprinkle BE studies, and beverage BE studies. With respect to all other types of BE studies, FDA’s guidance also offers advice on in vitro-in vivo correlation studies, pharmacodynamics methods, comparative clinical studies, and in vitro studies. All are suitable only in specific circumstances, FDA explained.
Other topics discussed in the guidance pertain to establishing bioequivalence for different dosage forms. Requirements differ if the drug is an oral solution as opposed to an immediate-release capsule or tablet, suspension, modified release product, or chewable tablet. The guidance also touches on “special topics,” like testing enantiomers and racemates, drug with complex mixtures, drugs with a long half-life, the effects of alcohol on modified release drugs, and drugs that are already found naturally in the body.
Companies have 90 days to comment on the study.
REFERENCE: RF Regulatory Focus; 4 DEC 2013; By Alexander Gaffney, RF News Editor