BE Recommendation Revision Again Demonstrates OGD Recognition of Q1 and Q2 Value

OGD has revised its bioequivalence (BE) recommendation for rifaximin 200 mg and 550 mg tablets. Quite interestingly, the requirements for products that are qualitatively and quantitatively (Q1 & Q2) the same as the reference listed drug (RLD) will have a reduced burden and may eliminate conducting bioequivalence studies with clinical endpoints (albeit pharmacokinetic [PK] studies and in vitro testing will still be needed).

The FDA states in its response to the innovator’s petition “Since the publication of the draft product-specific guidances [on the two products] in 2011 and 2012, the sensitivity of bioanalytical assays for rifaximin have improved significantly. As a result, we have revised the draft product-specific recommendations for both strengths of rifaximin tablets to include an option for demonstrating BE with in vitro dissolution studies and BE studies with PK endpoints for proposed generic rifaximin drug products that are Q1 and Q2 the same as Xifaxan. We [FDA] no longer believe that it is necessary that a BE study with clinical endpoints to be conducted to establish BE if the formulation of a proposed generic rifaximin generic product is Q1 and Q2 the same as Xifaxan.”  Thus, for these products, the FDA is now proposing that PK studies under fasting and fed conditions on the 200 mg product and acceptable in vitro dissolution testing on both strengths will satisfy BE requirements, as long as the formulations are dose-proportional and will permit a BE waiver for the 550 mg tablet product.

“If the test product formulations are not Q1/Q2 the same as the RLD with respect to inactive ingredients, BE should be established by conducting an in vivo study with clinical endpoints, in vivo study with PK endpoints, and in vitro comparative dissolution testing.”  The BE studies with clinical endpoints are to be conducted in travelers’ diarrhea for the 200 mg product and in irritable bowel syndrome with diarrhea (IBS-D) for the 550 mg product.  If the two strengths of the proposed generic product that are not Q1 and Q2 are proportionally similar, then a BE study with clinical endpoints on only the 550 mg product in IBS-D need to be conducted.  If the formulations of the 200 mg and 550 mg product are not dose-proportional, the BE studies with clinical endpoints will be expected for both strengths conducted using the appropriate indications for each strength.   See the entire revised BE recommendation here.

This is yet another example of a product that is only slightly systemically absorbed where FDA has formulated a BE recommendation that eliminated the conduct of BE studies with clinical endpoints in favor of other methods that are less burdensome.  Remember that comparative clinical BE studies are the least sensitive method for demonstrating BE, and FDA has been evaluating alternate methodology for such products to permit a more direct path to marketing, while assuring that BE determinations it makes are accurate.

The petitions referred to above are dockets FDA-2008-P-0300 and FDA-2016-P-3418, and FDA’s response can be found here. The FDA’s response addresses its reasoning for revision of the BE guidance, as well as addressing other issues (e.g., polymorphic form of the API) raised in the petitions.

Since it is possible that generic firms have already submitted ANDAs for this product (FDA’s Paragraph IV database cites a first-to-file date of 12/18/15 for the 550 mg product, but no date for the 200 mg product is listed), will firms be required to revise or redo BE studies to comply with the new guidance?  Will any firm that has the products under development, but not yet filed need to go back and redo studies or reformulate their products? Have the original pre-revised BE requirements been so stringent that no firm has been able to demonstrate BE through a clinical endpoint study?  These are obviously answers to questions that only those at the FDA or sponsors of applications for these products would know.