FDA Offers Specific Guidance on Bioequivalence Trials for Next Generation of 38 Generic Drugs

The US Food and Drug Administration (FDA) on Thursday unveiled 38 new specific recommendations on the types of bioequivalence trials generic drug companies should run in order to win approval for their abbreviated new drug applications (ANDAs).

The list targets what trials should be run by those developing a number of new generic oncology treatments, though many have yet to lose patent protection and some were recently approved, including Pfizer’s breast cancer drug Ibrance (palbociclib),  Eisai’s thyroid cancer drug Lenvima (lenvatinib mesylate) and Novartis’ basal cell carcinoma treatment Odomzo (sonidegib phosphate).

In deciding which guidance documents to issue, FDA’s Office of Generic Drugs (OGD) said in a report issued Wednesday that it considers the complexity of the formulation, ability to accurately measure its bioavailability at the site of action, scientific methods to demonstrate bioequivalence and previous experience with and knowledge of similar drugs.

OGD also takes into consideration the level of demand for such guidance, which is assessed through incoming requests and by analyzing the list of 100 top-selling drugs and other broadly used drugs.

That analysis shines through when it comes to some of the new guidance, particularly for generics of Novartis’ blockbuster heart failure treatment Entresto (sacubitril/valsartan) and Vertex’s pricey Kalydeco (ivacaftor) to treat cystic fibrosis.

Other specific guidance documents are for generics of Janssen’s HIV drug Prezcobix (Cobicistat; Darunavir Ethanolate), Eli Lilly’s Glyxambi (empagliflozin/linagliptin) tablets for adults with type 2 diabetes and Bristol-Myers Squibb’s Daklinza (daclatasvir dihydrochloride) to treat hepatitis C, among others.

“To successfully develop and manufacture a generic drug product, an applicant should consider that their  product is expected to be:  pharmaceutically equivalent to its reference listed drug (RLD), i.e., to have the same active ingredient, dosage form, strength, and route of administration under the same conditions of use,  bioequivalent to the RLD, i.e., to show no significant difference in the rate and extent of absorption of the active pharmaceutical ingredient;  and, consequently,  therapeutically equivalent, i.e., to be substitutable for the RLD with the expectation that the generic product will have the same safety and efficacy as its reference listed drug,” FDA says.

The updated guidance also includes six revised bioequivalence recommendations for ciprofloxacin/dexamethasone, cyclosporine, testosterone, ticagrelor and valganciclovir HCl. FDA now offers a total of 1435 specific recommendations for generic drug testing.

"To further facilitate generic drug product availability and to assist generic pharmaceutical industry with identifying the most appropriate methodology for developing drugs and generating evidence needed to support ANDA approval, FDA publishes product-specific recommendations describing  the Agency’s current thinking and expectations on how to develop generic drug products therapeutically equivalent to specific reference-listed drugs," FDA says. 

Product-Specific Recommendations for Generic Drug Development