The US Food and Drug Administration (FDA) has published a new draft guidance recommending various approaches when conducting bioequivalence (BE) and bioavailability (BA) studies in support of new and investigational drug applications.
What Does FDA Mean by BA/BE?
BA refers to the extent to which a drug is absorbed into the body and is thus available to act upon the drug's intended target, also known as the "site of action" (21 CFR 320.1[a]). For example, if a drug is ingested orally, it may be partially metabolized, leaving less of the drug to act upon the target site. Drugs that are administered intravenously, by contrast, are generally much more bioavailable. Other routes of administration include transdermal (such as skin patches), nasal (such as nasal sprays) and rectal (such as suppositories).
By extension, bioequivalence refers to the "absence of a significant difference" between the bioavailability-specifically the extent and rate of absorption-of two (supposed) pharmaceutical drug equivalents over the course of a period of time, at the same dose and under the same conditions.
Drugs that are deemed to be bioequivalent are, for regulatory purposes, essentially the same-a key requirement for generic drug products submitted under an abbreviated new drug application (ANDA).
What's This Guidance About, Anyways?
The draft guidance, Bioavailability and Bioequivalence Studies Submitted in New Drug Applications or Investigational New Drug Applications-also known as the NDA BA and BE Draft Guidance-is meant to clarify FDA's latest views on complying with 21 CFR 320.
That section, "Bioavailability and Bioequivalence Requirements," calls for all applicants of full new drug applications (NDAs) to either submit data measuring the in vivo bioavailability of a drug or data showing why BA data is unnecessary. It also calls for any sponsor of an ANDA to submit data establishing bioequivalence between the generic drug and the drug it references, known to FDA as the reference listed drug (RLD).
These data are crucial during various stages of FDA's regulatory approval process. For example, FDA will require any drug seeking approval to submit BA and BE data. Similarly, once a drug is approved by FDA, the agency will require BE testing after any major changes (such as to the manufacturing process) to ensure that the test drug product has not changed relative to the approved reference drug product.
Another example is when a company is advancing a drug through investigational testing. Companies often make changes to a drug product's manufacturing process during this time (known as scale-up changes), and testing is necessary to ensure that a product hasn't changed.
Who is this Guidance Meant for?
Unlike other guidance documents on BE, which are most often intended for sponsors of ANDAs, FDA's latest draft guidance is intended solely for sponsors of Investigational New Drug (IND) applications, NDAs and NDA supplements.
Accordingly, FDA said it has taken a slightly different approach in both its use of information and the recommendations it makes.
"In this endeavor, we use the totality of information available in the submission, which includes, among other things, information gathered using the principles of BE, exposure-response evaluations, and clinical trial results," FDA writes in the guidance. "The evaluation of BE in the generic drug context, by contrast, is used to support a determination that a generic product may be substituted for its reference listed drug, and involves consideration of different types of data permitted in an ANDA."
In other words: Access to a more cohesive set of data allows FDA to take a more streamlined approach toward evaluating data.
What Does the Guidance Recommend?
Accordingly, while ANDA applicants need to submit BE studies based on one cohort of patients who fasted before taking a drug and another who were fed, NDA and IND applicants only need to submit data from a fasting study.
"Fasting BE studies generally are sufficient, given the totality of information we consider in evaluating INDs, NDAs, or NDA supplements," FDA wrote.
The document goes on to explain the methods that sponsors of NDAs, INDs and NDA supplements should use to document BA and BE data, with a predominant focus on pharmacokinetic study data. Other approaches, including predictive in vitro testing, are also explored.
FDA's draft guidance also contains specific recommendations for solutions, immediate-release (IR), and extended-release (ER) products. Other "special" topics, such as the effects of alcoholic beverages on modified-release products, are also explored at length.
FDA also recommends that for pivotal BE studies, the test batch created for the study should be "representative of the production batches," or the larger of 100,000 units or 10% of the planned production batch size.
How Can I Shape This Guidance?
FDA is currently accepting comments on this draft guidance. Comments will be formally accepted until 60 days after its publication in the Federal Register, now set for 18 March 2014.
Bioavailability and Bioequivalence Studies Submitted in New Drug Applications or Investigational New Drug Applications