On March 23, 2010, President Obama signed into law a sweeping overhaul of the nation’s health care system. While provisions relating to health insurance reform received the attention of the national media, the law also includes significant provisions relating to biologic drugs. Specifically, § 7002 (the “Biological Price Competition and Innovation Act of 2009”) of H.R. 3590 (the “Patient Protection and Affordable Care Act”), lays out the framework for approval of follow-on biologics, or “biosimilar” biological products. The new law borrows heavily from the Hatch Waxman Act for small molecule generic drugs, but is different in many important ways. This Alert provides an overview of the newly enacted biosimilar regulatory approval pathway.¹

Biosimilarity and Interchangeability

First, the law provides that the Food and Drug Administration (FDA) will approve applications that demonstrate the biologic product is biosimilar to and interchangeable with the reference product.

“Biosimilar” is defined as a biological product that “(A) … is highly similar to the reference product notwithstanding minor differences in clinically inactive components” and for which “(B) there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency of the product.” “Interchangeable” is defined as a “biological product [that] may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”

Under the law, biosimilar product applications must demonstrate:

• the biological product is biosimilar to a reference product;
  
  
• the biological product and reference product utilize the same mechanism of action for the label claims, to the extent a mechanism is known;
  
  
• the conditions for which the biosimilar product applicant is seeking approval have been previously approved for the reference product;
  
  
• the route of administration, dosage form, and strength of the biological product is the same as those of the reference product; and
  
  
• the facility in which the biological product is produced meets certain specified requirements.

Biosimilarity is demonstrated by providing certain types of data:

• analytical study data “demonstrat[ing] that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components";
  
  
• animal study data, “including the assessment of toxicity”; and
  
  
• clinical study data “that are sufficient to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use.” Such data may include assessment of immunogenicity and pharmacokinetics or pharmacodynamics.

Interchangeability, under the law, is determined by a showing of safety, under which the FDA will determine if the proposed biological product (1) is biosimilar to the reference product; (2) “can be expected to produce the same clinical result as the reference product in any given patient”; and (3) for multi-dose products, the law requires a showing that switching between use of the biosimilar product and the reference product is as safe as using only the reference product.

Exclusivity

Under the new law, a biosimilar product cannot be approved by the FDA until 12 years after the approval date of the reference product. An additional 6 months of pediatric exclusivity is also available. For orphan drugs, the new law provides 7 years exclusivity (7.5 years with pediatric exclusivity).

Applications for marketing approval of a biosimilar product can be filed with the FDA 4 years after approval of the reference product.

The first biosimilar product filer will receive market exclusivity. For the first biosimilar product filer, exclusivity will be between 1 year and 42 months before another biosimilar biological product can be approved. Exclusivity for the first biosimilar filer is the earlier of:

• 1 year after the first commercial marketing of the first biosimilar product to be approved as interchangeable for that reference product;
  
  
• 18 months after either (i) a final court decision of patent litigation against the first biosimilar product filer or (ii) dismissal of a patent litigation action against the first biosimilar product filer;
  
  
• 42 months after approval of the first biosimilar product, if there has been patent litigation against the first biosimilar filer and that litigation is still ongoing; or
  
  
• 18 months after approval of the first biosimilar product if there has been no patent litigation against the first biosimilar filer.

Patent Litigation – Exchange of Patent Information

Under the new law, the filing of an application for approval of a biosimilar product triggers a series of requirements relating to patents, ultimately leading to potential patent litigation.

Access to Biosimilar Application is Mandatory

The new law requires that, within 20 days of FDA acceptance of an application for marketing approval of a biosimilar product, the applicant must provide the reference product sponsor a copy of the biosimilar application. The applicant must also provide “such other information that describes the process or processes used to manufacture the biological product that is the subject of such application.” Specific provisions regarding the confidential treatment of this information are also included in the law.

Exchange of Patent Information, Road to Litigation

The filing of the biosimilar product application triggers an exchange of patent information under the new law.

Within 60 days of receipt of the biosimilar product application, the reference product sponsor must provide “(i) …a list of patents for which the reference product sponsor believes a claim of patent infringement could reasonably be asserted” and “(ii) an identification of the patents on such list that the reference patent sponsor would be prepared to license.”

Next, within 60 days of receipt of the reference product sponsor’s list, the biosimilar product applicant must provide, on a claim-by-claim basis, (i) a statement that each listed patent is invalid, unenforceable, or will not be infringed by the biosimilar product; or (ii) a statement that the biosimilar applicant will not market the product until after the date the patent(s) expire. The biosimilar product applicant may also provide its own list of patents to which it believes a claim of patent infringement could reasonably be asserted by the reference product sponsor.

Finally, within 60 days of receipt of the biosimilar product applicant’s list and statement, the reference product sponsor must provide a statement, on a claim-by-claim basis, that explains how each claim will be infringed by the biosimilar product. This statement must also include a response to the biosimilar product applicant’s assertions regarding invalidity or unenforceability of the patent(s).

Prior to any patent litigation, the law requires the parties to enter good faith negotiations to determine which, if any, patents will be the subject of a patent litigation suit. If the parties reach agreement on the patent list, the reference product sponsor must file a complaint for patent infringement within 30 days of the agreement. If the parties do not agree to a patent list, the law provides that they exchange lists of patents they believe should be the subject of litigation. The reference product sponsor then must file a complaint within 30 days after the exchange of the patent lists. The law also provides a public notification provision of the litigation, whereby the biosimilar applicant must provide FDA with a copy of the complaint, which the FDA will then publish.

Commercial Marketing and Preliminary Injunctions

The law also mandates notice provisions with regard to preliminary injunctions, should a biosimilar applicant decide to launch its product prior to the resolution of patent litigation. Specifically, the biosimilar applicant must notify the reference product sponsor at least 180 days before the date of first commercial marketing of the biosimilar product. Upon receipt of such notice, the reference product sponsor may seek a preliminary injunction to prevent the biosimilar applicant from manufacturing or selling the product.

Declaratory Judgments

The law also sets out circumstances under which the parties may file a declaratory judgment action. These situations are generally triggered by the failure of one of the parties to follow the exchange of information provisions described above. The law generally prohibits declaratory judgment actions if each party is providing the patent information required by the law.

FDA Guidance

FDA will be issuing proposed guidance to implement the law. There are several areas that stakeholders will closely watch. For one, the law does not define further or describe what is meant by “highly similar.” Presumably, this concept will be the subject of guidance documents from the FDA. In addition, the law provides that the FDA may determine that one of the requirements for showing biosimilarity is unnecessary. Because the law requires a public comment period on FDA proposed guidance documents relating to the FOB law (see § (k)(8)(B) of the law), stakeholders may have an opportunity to influence the regulatory provisions.

Preparing for Biosimilars

In view of these new provisions for the approval of biosimilar products, it is paramount that companies that are developing or marketing biological products inventory and evaluate their patent estate. We will provide implementation notes for such patent estate evaluations in future Alerts.

¹ Any amendments to H.R. 3590 that would affect the biosimilar product framework are not discussed here. We will provide further updates as amendments, if any, are enacted.