If changes are made to the product formulation (such as solution form instead of emulsion versus intravenous, subcutaneous, intrathecal, intranasal or oral or a different concentration is formulated) after receiving orphan designation and prior to NDA submission, will the approved NDA still qualify for exclusivity?

Orphan drug designation is generally conferred to the active moiety rather than the product formulation; therefore, changes to the product formulation should not generally affect orphan drug designation status.
The first sponsor to bring an active moiety to market receives the benefits of exclusivity if that sponsor has orphan designation. If the sponsor subsequently makes a change in formulation to the original product, which was designated and approved for marketing, we consider the sponsor to still have designation for the active moiety. But the sponsor will not receive a new term of exclusivity upon approval of the changed formulation unless the sponsor can demonstrate that the changed formulation is clinically superior to the original approved product.