FDA refreshes bioequivalence guidance for generic drugs

Generic drug makers received a refreshed draft guidance from the US Food and Drug Administration on Friday; the guidance updates some recommendations on the conduct of bioequivalence (BE) studies that have pharmacokinetic endpoints.
 
In announcing the updated draft guidance’s availability, FDA said that the document is meant to "clarify the agency’s recommendations regarding BE information submitted in an [abbreviated new drug application] submission, provide assistance to potential ANDA applicants, and support access for patients to lower cost, high quality medicines.” The new revision updated a draft originally published in December 2013. (RELATED: FDA Updates Bioequivalence Testing Guidance Intended for Generic Drug Manufacturers, Regulatory Focus 04 December 2013)
 
Applicants who are planning an abbreviated new drug application (ANDA) submission should also consult relevant product-specific guidances for detailed information about which BE studies should be completed as part of the submission process, noted FDA.
 
The revised draft is rearranged so that some material that was originally in an attachment is now in the main body of the guidance, while other material has been moved to one of two appendices. The first appendix largely parallels content of an attachment to the first draft, and provides general guidelines for study conduct.
 
The second appendix is new; it provides a step-by-step guide to for using a reference-scaled average BE approach in statistical analysis of BE for highly variable drugs.
 
Revisions to the 2013 draft clarify that ANDA applicants must submit results of all BE studies conducted on a drug substance that has the same formulation as the proposed drug product. The revised guidance also clarifies the situations when a replicate crossover study design might be appropriate.
 
The document’s guidance on selection of the study population now includes an expanded explanation of how a BE assessment in adults can be used to support BE assessment in pediatric populations, noting that an accompanying justification should “include information supporting that the inactive ingredients in the proposed products are appropriate for use in the pediatric population.”
 
Additional information is also included about calculating extent of exposure for single-dose studies, and revisions were made to recommendations for calculating partial exposure as well. The revised draft guidance provides additional considerations for when a fed BE study should be conducted in addition to a fasting BE study, and for the conduct of sprinkle BE studies.
 
The revised draft also includes additional considerations for BE testing for delayed-release products, and clarifies the conditions under which additional strengths of modified-release products are considered to have bioequivalency. More detail regarding other delivery methods such as orally disintegrating tablets, sublingual tablets, and transdermal delivery is also included in the updated draft guidance.
 
The section on in vitro dissolution testing includes reference to additional guidance issued after the original draft’s 2013 publication date.
 
“FDA is publishing this revised draft guidance to solicit public comments on the topics discussed in the guidance,” noted the agency in its announcement.
 
FDA