11 • animal studi t es (including the assessment of toxicity); and • a clinical study t or studi t es (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) sufficient to demonstrate safety, purity and potency in one or more conditions for which the reference product is licensed and intended to be used. In addition, an application must include information demonstrating that: • the proposed biosimilar produc d t and reference product utilize the same mechanism of action for the condition(s) of use prescribed, recommended, or suggested in the proposed labe a ling, but only to the extent the mechanism(s) of action are known for the reference product; • the condition or conditions of use prescribed, recommended, or suggested in the labe a ling for the proposed biosimilar product have been previously approved for the reference product; • the route of administration, the dosage form, and the strength of the proposed biosimilar product are the same as those for the reference product; and • the facility in which the biological product is manufact f ur t ed, processed, packed or held meets standards designed to assure that the biological product continues to be safe, pure, and potent. Biosimilarity means that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and that there are no clinically meaningful f differences between the biological product and the reference product in terms of the safety, purity, and potency of the product. In addition, the law provides for a designation of “interchangeability” between the reference and biosimilar products, whereby the biosimilar may be subs u tituted for the reference product without the intervention of the health care provider who prescribed the reference product. The higher standard of interchangeability must be demonstrated by information sufficient to show that: • the proposed product is biosimilar to the reference product; • the proposed product is expected to produce the same clinical result as the reference product in any given patient; and • for a product that is administered more than once to an individual, the risk to the patient in terms of safety or diminished effi f cacy of alternating or switching between the biosimilar and the reference product is no greater than the risk of using the reference product without such alternation or switch. FDA approval is required before a biosimilar may be marketed in the United States. In addition, as with BLAs, biosimilar product applications will not be approved unless the product is manufact f ur t ed in facilities designed to assure and preserve the biological product’s safety, purity and potency. The timing of final FDA approval of a biosimilar for commercial distribution depends on a variety of factors, including whether the manufact f ur t er of the branded product is entitled to one or more statut t ory r exclusivity periods, during which time the FDA is prohibited from approving any products that are biosimilar to the branded product. The FDA cannot approve a biosimilar application for twelve years from the date of first licensure of the reference product. Additionally, a biosimilar product sponsor may not subm u it an application for four years from the date of first licensure of the reference product. A reference product may also be entitled to exclusivity under other statut t ory r provisions. For example, a reference product designated for a rare disease or condition (an “orphan drug” r ) may be entitled to seven years of exclusivity, in which case no product that is biosimilar to the reference product may be approved until either the end of the twelve-year period provided under the biosimilarity statut t e or the end of the seven-year orpha r n drug r exclusivity period, whichever occurs later. In certain circumstances, a regulatory exclusivity period can extend beyond the lifef of a patent, and thus block biosimilarity applications from being approved on or afte f r the patent expiration date. In addition, the FDA may under certain circumstances extend the exclusivity period for the reference product by an additional six months if the FDA requests, and the manufact f ur t er undertakes, studi t es on the effe f ct of its product in children, a so-called pediatric extension.