The US Food and Drug Administration’s (FDA) difficulties in approving generic versions of complex products were front and center in Commissioner Scott Gottlieb’s comments at FDA’s Generic Drug Science Day on Tuesday.
Complex generic drugs – often declared complex because of their unique formulations (such as ophthalmic suspensions like with Allergan’s Restasis (cyclosporine), gels or others like Janssen’s chemotherapy Doxil), active ingredients (including peptides or polymeric compounds), routes of delivery (i.e. inhaled drugs like GlaxoSmithKline’s Advair) or drug-device combo products (i.e., why is there only an authorized generic for Mylan’s EpiPen?) – can be especially hard for the agency to approve.
In some cases, Gottlieb noted, traditional bioequivalence and bioavailability studies are not adequate to support approval, while in others, there may not be adequate scientific principles to reliably measure all of a treatment’s local effects.
As part of efforts to help speed approvals of complex generics and building off the release of product-specific guidance for companies and the approval of Mylan’s first generic version of Copaxone (glatiramer acetate injection), Gottlieb said FDA is working to finalize draft guidance released in January on referencing approved drugs in abbreviated new drug application (ANDA) submissions.
"The guidance lays out how generic applicants should consider when design differences between a generic version of a branded drug could impact the clinical effect or safety profile of the generic product, and thus the substitutability of the generic medicine," Gottlieb said. "The final guidance clarifies new policies related to these situations. This includes a principle we’re setting out that allows a generic product to have certain labeling differences from the branded product – if such labeling changes stem from permitted design differences."
As the US waits for generic and less expensive versions of Restasis, Advair, Pfizer’s blockbuster cream Premarin, Shire’s ulcerative colitis treatment Lialda (mesalamine), Merck’s near-blockbuster NuvaRing and Jazz Pharmaceuticals’ sleep disorder treatment Xyrem (sodium oxybate), Gottlieb said FDA is also developing guidance "with the aim of clarifying ‘sameness’ requirements for ANDAs. We believe that guidance in this area may be particularly helpful for complex generics, including drug-device combination products."
In October, FDA also released draft guidance on ANDAs for certain highly purified synthetic peptide drug products.
But each product can have a unique situation, and companies such as Allergan, will continue submitting citizen petitions to raise questions with FDA regarding its approval of complex generics.
Remarks by Dr. Gottlieb at FDA's Generic Drug Science Day
Product-Specific Guidances for Generic Drug Development
New Insights for Product Development and Bioequivalence Assessments of Generic Orally Inhaled and Nasal Drug Products
Demonstrating Equivalence of Generic Complex Drug Substances and Formulations