The regulator expressed concerns about the potential for immunogenicity that might result from a possible interaction between calcitonin, derived from salmon, and chlorobutanol, the preservative in Nastech's formulation which is also used in many nasal sprays already on the market.
Nevertheless, such concerns are usually reserved for biosimilar drugs and Nastech had filed an abbreviated new drug application (ANDA) on the assumption that calcitonin would be treated as a generic.
"We were completely surprised when the FDA asked us for antigenicity data because this information cannot be used in a generic drug application," Gordon Brandt, Nastech's executive vice president of clinical research and medical affairs, told In-PharmaTechnologist.com.
"The ANDA was accepted as generic and the FDA reviewed it for 30 months before letting us know of their concerns."
Generic ANDAs are scrutinised less vigorously than biosimilar ANDAs because all a generic maker must do is present laboratory evidence that its copy is chemically the same as the original and human clinical tests showing that the generic behaves like the original in the bloodstream, without any additional clinical data.
But since calcitonin is a peptide, why didn't Nastech treat it as a biosimilar? At the heart of the issue is nomenclature and the definition of "biogeneric" and "biosimilar" in the US.
The FDA has already approved several generic versions of biologic molecules, like Sandoz's human growth hormone called Omnitrope (somatotropin), not as biogeneric but as "sufficiently similar" to products already approved, using the term "follow-on protein" instead of the term "biosimilar" used in Europe.
Intriguingly, the fact that a molecule is biologic does not automatically make its generic version a biosimilar - insulin is treated by the FDA not as a biosimilar but as a normal generic.
This is because a protein's molecular weight as well as the complexity of its structure are factored in before a peptide is characterised as a biosimilar; the higher the protein's molecular weight and the more complex its structure, the likelier it is to be seen as a biosimilar.
Thus, since calcitonin has a lower molecular weight than insulin, no tertiary or quaternary structure and is not glycosylated, Nastech believed it would also not be seen as a biosimilar but as a normal generic.
The reason the FDA decided to change its approach to calcitonin more than two years after the ANDA was submitted may have to do with a case that in 2002 angered the US public and embarrassed the agency - Johnson & Johnson's anemia drug Eprex (epoetin).
Even small changes in a biologic production process can have dramatic consequences on a product's safety and efficacy, so a manufacturing glitch at Johnson & Johnson's facility in Puerto Rico resulted in the rubber compound in the pre-filled syringe interacting with the administered erythropoietin and triggering an autoimmune response which lead to pure red cell aplasia, a lethal condition.
Nastech believes that the FDA may now feel that a similar interaction between calcitonin and chlorobutanol may lead to allergic reactions, though such a proposition is theoretical and no allergic reactions have been observed in any of the clinical trials conducted by Nastech.
"Unlike with epoetin, calcitonin-salmon is not the same as the human form so any antibodies it creates in the body do not target native calcitonin," Brandt explained.
"There is no data to suggest this changes when calcitonin is formulated together with chlorobutanol."
The Bothell-based company explored the possibility of using no preservative but such technology is still in development and trying to get the first preservative-free nasal spray in the US approved by the FDA is a risky business, Brandt said.
The reason Nastech decided to use a different preservative from benzalkonium chloride (BKC) that Novartis uses in the branded version of the drug is because of the discomfort BKC can create and possible adverse effects on the nasal mucosa, a concern particularly strong in Europe.
The company is now caught in catch-22 situation because even if it submits additional immunogenicity data, the FDA may not be able to process it under the generic application pathway and a new drug application as a biosimilar may be required.
Meanwhile, Nastech's two manufacturing sites in Washington and New York have passed chemistry, manufacturing, and control (CMC) inspections and are waiting to start production on the spray.
They may now have to wait for a while, like everyone in the pharmaceutical industry who expects clarity in the FDA's approach of biosimilar molecules.