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# Cubist Dificid Petition Approved, Denied
- URL: https://www.fdaweb.com/cubist-dificid-petition-approved-denied/
- Published: 2016-08-23T12:00:00.000Z
- Updated: 2026-09-14T21:26:07.000Z
- Author: David McFarland
- Tags: Drugs, #legacy-id-D5136589

FDA has approved in part and denied in part a Cubist Pharmaceuticals 5/7/15 petition asking that it refuse to accept for filing, for substantive review, or for approval any ANDA or 505(b)(2) NDA referencing Cubist’s Dificid (fidaxomicin) 200 mg film-coated tablets that does not contain scientifically appropriate data demonstrating bioequivalence. Cubist said that FDA should require an applicant to show **(1)** a bioequivalence study using appropriate, validated clinical endpoints conducted in patients with *Clostridium difficile*\-associated diarrhea similar to pivotal studies included in Dificid’s approved labeling; **(2)** a bioequivalence study with pharmacokinetic endpoints conducted under both fed and fasted conditions; and **(3)** *in vitro* dissolution tests. FDA should have an advisory committee meeting, Cubist said, if it had insufficient evidence to establish bioequivalence guidance or wanted to propose an alternative set of criteria.

The agency [response](https://www.regulations.gov/contentStreamer?documentId=FDA-2015-P-1595-0005&attachmentNumber=1&disposition=attachment&contentType=pdf&ref=fdaweb.com) says it recommends that an applicant seeking approval of a generic product referencing Dificid that demonstrate it is as Q1/Q2 as the reference-listed drug, and should conduct *in vivo* bioequivalence studies with pharmacokinetic endpoints under fed and fasted conditions and comparative *in vitro* dissolution studies under multiple pH conditions to establish bioequivalence.

For a product that is not Q1/Q2 to Dificid, it says, differences in the type and amount of excipients may affect the metabolism, absorption, and antibacterial activity of the drug substance at the site of action. In such an instance, it says, sameness in the *in vitro* dissolution profile and sameness in plasma PK cannot ensure the same amount of available drug in the GI tract. So a bioequivalence study with clinical endpoints is recommended to demonstrate bioequivalence for fidaxomicin test product formulations that are not Q1/Q2.

The agency says that the clinical endpoints the company proposed may not always be appropriate for bioequivalence evaluation for non-Q1/Q2 generic fidaxomicin products referencing Dificid. FDA says it disagrees with Cubist’s position that a bioequivalence study with clinical endpoints should compare the generic drug, the reference drug, and a placebo. It recommends that any clinical endpoint study use only active treatment.

For 505(b)(2) applications, the letter says, the types of data demonstrating the efficacy and safety of a fidaxomicin product will vary depending on the specific change in the product being proposed in the NDA. Thus, FDA says, it is not feasible to establish in advance a uniform set of requirements for the evidence that should be provided.

The letter also rejects Cubist’s suggestion that the agency’s rifaximin draft guidance should determine bioequivalence methods for generic fidaxomicin products referencing Dificid, and rejects the call for an advisory committee meeting.