Regulatory Focus™ > News Articles > FDA Looks to Confront Potential Bioequivalence Problems in Generic Anemia Product

FDA Looks to Confront Potential Bioequivalence Problems in Generic Anemia Product

Posted 17 July 2013 | By Alexander Gaffney, RAC

In recent months, the US Food and Drug Administration (FDA) has grappled with bioequivalency problems between the generic versions and reference version of one drug, Wellbutrin XR 300 mg (bupropion HCl). Now, it may be homing in on a similar problem involving an anemia drug, according to a contract solicitation posted by the agency Tuesday.


Generic drugs were first afforded an expeditious and formal path to market under the Drug Price Competition and Patent Term Restoration Act of 1984, better known as the Hatch Waxman Act. The act created section 505(j) of the Federal Food, Drug and Cosmetic Act (FD&C Act), permitting companies to offer "generic" versions of an already-approved drug provided the original drug's patents had expired and the generic drug was bioequivalent to the reference listed drug (RLD) within certain acceptable limits.

For a generic drug to be bioequivalent to an RLD, data must show the former to have the same biological availability with respect to the rate of absorption and availability after administration at the same molar dose. Per a 2003 FDA guidance document on bioequivalence, the term is taken to mean:

"[T]he absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study."

Drugs are found to be bioequivalent - that is, not "significantly different" - if they exhibit a mean Cmax, AUC(0-t) and AUC(0-∞) of 80% to 125% of the RLD (90% confidence interval).

The guidance goes on to note that bioequivalence studies are a "critical component" of generic drug submissions, also known as abbreviated new drug applications (ANDA).

But while bioequivalence testing is generally useful in showing a similar safety and efficacy profile between two drugs, it can't account for all differences in all drugs.

New Problems, or Just Speculation?

Since the passage of the Hatch-Waxman Act, FDA has released hundreds of draft and final guidance documents regarding bioequivalence recommendations for specific products. These documents outline the drug's active ingredients, the form of the drug to be studied, the recommended studies needed to show bioequivalence and potential waiver criteria, and are meant to illustrate the FDA-recommended path to expeditious approval for an ANDA.

One guidance that does not yet exist is one for Ferrlecit (sodium ferric gluconate iron complex), an iron injection product used to help treat anemia, and particularly in patients with chronic kidney disease (CKD). In March 2011, FDA approved a generic version of Ferrlecit known as Nulecit.

This approval raised some novel questions, FDA explains in a solicitation notice on the Federal Business Opportunities (FBO) website.

"It has been suggested that generic iron formulations could have higher levels of labile iron, leading to the formation of a greater amount of nontransferrin-bound iron (NTBI) in vivo than the reference listed drug (RLD) that would potentiate oxidative stress and inflammation, then resulting in direct cellular damage and possibly increasing the risk of atherosclerotic disease," it wrote.

In other words, the generic version of the drug - despite having met bioequivalence standards - may not be as safe as the RLD.

FDA now says it wants a "battery of physicochemical characterization tests" to be conducted to "ensure comparable tissue distribution and no more in vivo labile iron leakage from generic formulations than that from the RLD."

"Well controlled, prospective studies that investigate iron tissue distribution in preclinical species and compare non-transferrin bound iron levels between brand and generic in hemodialysis patients may confirm the agency's approval criteria and help address the public concerns," it concluded.

If confirmed, the problem would be at least the second in the last year for FDA regarding a generic drug. In March 2013, FDA formally withdrew approval for Impax Laboratories' Budeprion XR 300 mg, a generic of Wellbutrin XR 300 mg, after testing conducted by FDA showed the two were not sufficiently bioequivalent. FDA has since updated the bioequivalence standards for that drug, instituting new testing requirements at the 300 mg dose level and others.

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