Senators Kennedy, Hatch, Clinton, and Enzi announced legislation authorizing the FDA to approve a follow-on version of biologic therapies. The legislation, the Biologics Price Competition and Innovation Act of 2007, includes standards for the FDA to approve follow-on biologics as well as a period of exclusivity for the brand name drug company.

The draft compromise bill tries to resolve some of the sticky issues surrounding the extent of trials a follow-on biologic would need prior to approval, whether a biosimilar could be deemed an interchangeable alternative to a brandname biologic, and the length of time an innovator biologic would be protected from competition.

A biologic is manufactured in a living system such as a microorganism, or plant or animal cells. Most biologics are very large, complex molecules or mixtures of molecules while a small molecule drug is typically manufactured through chemical synthesis. It is difficult to characterize a complex biologic by testing methods available in the laboratory. Therefore, for biologics, the product may be too closely tied to the process to separate the two.

Unlike small molecule drugs, which are approved under the FDCA, most biologics are approved under the Public Health Service Act (PHSA). The FDCA provides a framework for approving generic copies of small molecule drugs, but no commensurate legal framework is currently in place for approving follow-on biologics either under the FDCA or under the PHSA. The complexity of biologics makes it impossible to analyze them in a laboratory to the degree possible with chemical drugs, and to show without clinical trials that one biologic has the same safety and effectiveness profile as another.

To be approved as a generic, a drug must have the same active ingredient, strength, dosage form, and route of administration as the reference drug, and it must also be “bioequivalent.” This means that generic drugs are the same chemically as their innovator counterparts and that they act the same way in the body. The bioequivalence of the generic drug is demonstrated through relatively simple analyses such as blood level testing, without the need for human clinical trials. In approving a generic drug under 505(j) of the FDCA, FDA determines that the generic is “therapeutically equivalent” to the innovator drug, and is interchangeable with it.

FDA has stated that it has not determined how interchangeability can be established for complex proteins. Historically, FDA has permitted interchangeability only when two products are “therapeutic equivalents.” However, when the follow-on manufacturer establishes a new manufacturing process, beginning with new starting materials, it will produce a product that is different from and not therapeutically equivalent with that of the innovator. Because of the complexity of biologics, the only way to establish whether there are differences that affect the safety and effectiveness of the follow-on product is to conduct clinical trials.

Recent approvals of follow-on biologics by the FDA have been limited to those few biotechnologically derived products such as human growth hormone and certain insulin products approved under the New Drug Approval provisions of the Food, Drug, and Cosmetic Act, such as Novartis’ Sandoz approval of a 505(b)(2) NDA for its Omnitrope® version of Pfizer’s Genotropin® human growth hormone. While not a true generic application, a 505(b)(2) NDA allowed Sandoz to submit less than a full NDA. The FDA has previously taken the position that it lacks the authority to approve generic biologics under the PHSA.

The Act amends section 351 of the Public Health Service Act to provide for an approval pathway for safe biosimilar and interchangeable biological products (relying in part on the previous approval of a brand product) while preserving the incentives that have fueled the development of these life-saving medicines.

Approval Process

A biosimilar applicant is required to demonstrate that there are no clinically meaningful differences in safety, purity and potency between its product and the brand product. A demonstration of biosimilarity includes analytical data, animal testing and one or more clinical studies, unless such a requirement is determined by the FDA to be unnecessary.

FDA may approve a biosimilar product as interchangeable, meaning it can be substituted for the brand product without the intervention of the health care provider who prescribed it. Showing interchangeability requires evidence that the biosimilar product will produce the same clinical result as the brand product in any given patient and that it presents no additional risk in terms of safety or diminished efficacy if a patient alternates or is switched between products.

The legislation allows, but does not require the FDA to issue guidance documents to inform with the public of the standards and criteria the agency will use in approving biosimilar and interchangeable products. Development of these guidance documents will require public input. Applications can be filed in the absence of guidance documents.


The Act provides incentives for the development of both new life-saving biological products and interchangeable biosimilar products: 12 years of data exclusivity for the brand company during which a biosimilar product may not be approved, and 1 year of exclusivity for the first interchangeable biological product.

Patent Resolution

The legislation includes a multi-step process to identify and resolve patents that the biosimilar product may infringe. The biosimilar applicant must provide its application and information about its manufacturing process to the brand company. A series of informational exchanges then occur in which the biosimilar applicant and the brand company identify patents in question and explain their views as to their validity or infringement.

The two parties then either agree to a list of these patents to be litigated first or exchange lists when they can’t, and the brand company must then sue the biosimilar applicant within 30 days to defend them. If the brand company wins a final court decision that a patent is valid and infringed by the biosimilar product before the 12 year data exclusivity has run, the court must enjoin infringement of the patent until it expires. For identified patents not included in this initial litigation, the biosimilar applicant must give the brand company notice 180 days before it intends to launch its product, and the brand company may then seek a preliminary injunction to block the launch.

If the brand company fails to identify a patent, it can’t later enforce it against the biosimilar product. If it fails to defend a patent identified for initial litigation, the brand company may only later receive a reasonable royalty. If the biosimilar applicant fails at any step to do what it is required to do, the brand company may immediately defend its patents.

Legal Issues

The FDA has taken the position that each biologic is unique and inexorably linked to and inseparable from the manufacturing processes used in its creation. Complex operational and proprietary details of the manufacturing processes are central to and define the identity and unique molecular safety and effectiveness attributes of each biologic. Even if it were possible to establish “sameness” of biologics without clinical trials, it might be necessary for agency reviewers to examine trade secret data concerning the manufacturing processes of the innovator to perform a comparative assessment about “sameness.”

The bill is likely to be approved by the Senate Health, Education, Labor and Pensions Committee when it meets on June 27th.

Press statement:

Read the draft legislation here: Biologics Price Competition and Innovation Act

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  1. […] from the AMMA here. See the Biotechnology Industry Organization (BIO) fact sheets here. More here: Draft Bill Lays Down Path to Follow-On Biologics. Posted June 4th, 2008 by Stephen Albainy-Jenei in Biogenerics, Biotech, Biotech News | […]