On Capitol Hill, U.S. lawmakers are considering legislation that would authorize the U.S. Food and Drug Administration (FDA) to approve generic versions of biological products. Representative Henry Waxman (D, CA), of “Hatch-Waxman” fame, has introduced the “Access to Life Saving Medicine Act” (H.R. 1038) to advance this change to U.S. law. In introducing the legislation, Rep. Waxman referred to FDA’s approval of abbreviated applications for follow-on versions of several uncomplicated biotech products, and stated, “the science in this field is evolving rapidly, promising the ability to approve copies of more complex biotech products in the future.” The bill addresses key areas of follow-on biologic regulation, including the submission of comparable biological product applications, FDA review and approval of such applications, interchangeability determinations and exclusivity, final action on applications, and patents. Several of these bill items are described in greater detail below.

Review and Approval

The “Access to Life-Saving Medicine Act” would amend the Public Health Services Act to authorize FDA approval of “abbreviated biological product applications,” an abbreviated application for a license of a biological product containing the same, or similar, active ingredient as a reference product. Under the bill, the abbreviated biological product application would be required to include data demonstrating that the biological product is “comparable” to or “interchangeable” with the reference product. A biological product would be considered “comparable” in the absence of any clinically meaningful differences between the follow-on and reference products in terms of the product’s safety, purity, and potency based on chemical, physical, and biological assays as well as other nonclinical data and clinical study data necessary to confirm safety, purity, and potency in at least one condition of use of the licensed reference product. A biological product would be considered “interchangeable” with respect to the condition involved if it is comparable to the reference product and can be

expected to produce the same clinical result as the reference product in any given patient.

A submission would also require data demonstrating that the biological product and reference product contain “highly similar principle molecular structural features.” However, the bill makes allowances for “minor differences in heterogeneity profile, impurities, or degradation patterns.” The bill would mandate that FDA find the following types of products to contain highly similar principle molecular structural features:

• Two protein biological products with structural differences due solely to post-translational events, infidelity of translation or transcription, or minor differences in amino acid sequence.

• Two polysaccharide biological products with similar saccharide repeating units, even if the number of units differ or there are differences in post-polymerization modifications.

• Two glycosylated protein products with structural differences due solely to post-translational events, infidelity of translation or transcription, or minor differences in amino acid sequence, and if they had similar saccharide repeating units, even if the number of units differ or there are differences in post-polymerization modifications.

• Two polynucleotide biological products with identical sequence of purine and pyrimidine bases (or their derivatives) bound to an identical sugar backbone.

• Closely related, complex partly definable biological products with similar therapeutic intent, such as two live viral products for the same indication.

The bill recognizes that this list is not all-inclusive: FDA may find two biological products to contain highly similar principle molecular structural features based on data and information characterizing the two products.

Additional materials required for an application include data demonstrating the two products utilize the same mechanism of action (to the extent the reference product’s mechanism is known); information showing the conditions of use in the proposed labeling have been approved for the reference product; information showing the route of administration, dosage form, and strength are the same as the reference product; and data demonstrating that manufacturing, processing, packing, and holding facilities are designed to assure the product is safe, pure, and potent.

H.R. 1038 would require FDA to take final action on an abbreviated biological product application within eight calendar months of submission or 180 days following FDA notification that the application has been accepted, whichever is earlier. However, the final action date may be extended for a period of time as agreed to by FDA and the sponsor in a jointly-executed written agreement. FDA would also be required to issue a comparable biological product license for all conditions of use of the reference product for which the applicant has demonstrated comparability. Exceptions to this general requirement would be if the data submitted is insufficient in one of nine enumerated ways related to the scientific evidence submitted. For example, being insufficient to show that the biological product is comparable or to show the biological product and its reference contain highly similar principal molecular structures.

Interchangeability and Exclusivity

Under the bill, a sponsor may submit information to demonstrate the interchangeability of its comparable biological product and a reference product as part of the original application or as a supplement. Importantly, the bill calls for FDA to establish and publish guidance to sponsors regarding the standards and requirements for demonstrating interchangeability. Once FDA issues a product license for a comparable biological product, it will be required to publish a determination regarding the product’s interchangeability with the reference product. If FDA determines the products are interchangeable, the sponsor may then request that the product label include a statement that the product is interchangeable with the reference product.

In general, if an abbreviated biological product application relies on the same reference product for which a prior biological product has received a determination of interchangeability for any condition of use; FDA may not make an interchangeability determination for any condition until the earlier of:

1) 180 days after the first commercial marketing of the first approved interchangeable comparable biological product;

2) one year after a final court decision, including dismissal, on all patents in an action against the first approved applicant; or

3) 36 months after approval of the first product if litigation is still ongoing or one year after approval, if the first applicant has not been sued.

Thus, for a subsequent biological product demonstrating comparability to a reference product for which FDA has already approved a comparable, interchangeable biological product, FDA may not issue a product license and must defer publishing any interchangeability determination until the end of the 180-day exclusivity period.

In discussing interchangeability and exclusivity, the bill addresses the potential for “authorized” generic biologics. The bill explicitly provides that no biological license holder may manufacture, market, sell, or distribute a “rebranded” interchangeable biological product, directly or indirectly, nor can such license holder authorize another company to do the same. Under the bill, a “rebranded interchangeable biological product” is any rebranded interchangeable version of the reference product that the reference product’s license holder seeks to market, sell, or distribute. The definition does not include any product that will be marketed by the company eligible for exclusivity or any product following expiration of exclusivity.

Patents & Notification

Under the bill, an applicant may request patent information from the reference product’s sponsor at any time, including during initial development. The reference product license holder would be required to provide the applicant with a list of all patents owned by or licensed to it that relate to the reference product, including patents claiming the approved biological product, any method of using such product, any component of such product, or any method or process of manufacturing the product or component. Following the request, the license holder would have a continuing obligation to update the list for a period of two years. The bill allows the license holder to demand as much as $1,000 to offset the costs of responding.

Following submission of an application, the generic biologic sponsor may notify the reference product license holder of the application with respect to any patent identified in the request described above, by sending a notice to both the license holder and patent owner. The notice must include a detailed statement that the patents involved are invalid, not enforceable, or will not be infringed by the commercial sale of the product. The notice must also identify at least one judicial district in which the applicant consents to being sued.

Per the bill, the holder or patent owner may bring action for infringement within 45 days of receiving notice, but only as to those patents included in the notice and only in the district identified in the notice. A notice recipient may bring action for a declaration of infringement, validity, or enforceability for any patent not identified in the notice only after commercial marketing of the product.

At the outset, the bill has garnered public support from a variety of sources, including Teva, the Generic Pharmaceutical Association (GPhA), American Federation of Labor and Congress of Industrial Organizations (AFL-CIO), and General Motors. While opponents of the bill have been relatively quiet thus far, expect the debate over generic biologics — including the standards for comparability and interchangeability — to heat up as the House Committees on Energy and Commerce and the Judiciary consider the legislation in the coming

months.  

By Gary C. Messplay, J.D., and

Colleen Heisey, J.D., M.P.H.

Hunton & Williams, LLP

Gary C. Messplay is a partner in the Washington, D.C. office of Hunton & Williams LLP (www.hunton.com), where he is head of the law firm’s Food and Drug Practice. He can be reached at [email protected] Colleen Heisey is an attorney in the firm’s Food and Drug Practice.  • NEW BRUNSWICK, NJ

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