Written by Gwilym Attwell, Birgit Millauer, and Song Ren.
In March 2009, Congressional representatives have introduced two competing bills to enable the FDA to approve generic versions of biologics. These bills appeared swiftly after President Obama’s 2010 budget specifically called for such a process. Although Congress has considered similar legislation in past years,[i] given the current level of presidential and bipartisan support, enactment of a generic approval route for biologics appears quite likely.
Representative Waxman (CA), along with Representatives Deal (GA), Emerson (MO), and Pallone (NJ), introduced the first bill, H.R. 1427 (the “Waxman Bill”) on March 11, 2009. On March 17, 2009, Representatives Eshoo (CA), Inslee (WA), and Barton (TX) introduced a competing bill, H.R. 1548 (the “Eshoo Bill”). Both bills are bipartisan.
Generic manufacturers have voiced support for the Waxman Bill, while pioneers have come out in favor of the Eshoo Bill. Not surprisingly, the two proposals differ on several points where the interests of generics and pioneers diverge. Where the Waxman Bill proposes a five year exclusivity for pioneers of a new biologic, the Eshoo Bill proposes a minimum of 12 years for pioneer exclusivity. Where the Waxman Bill seeks to limit the filing of FDA citizen petitions that might delay approval, the Eshoo Bill elevates the importance of FDA guidance documents in the approval process. Notably, both proposals contain significant differences from the 1984 Hatch-Waxman legislation, which controls the generic approval of small molecule drugs. For example neither bill utilizes the Orange Book or an equivalent to list relevant patents, and neither includes an express 30 month stay for patent litigation.
The key features of both bills are discussed in further detail below. The table at the end also provides a convenient comparison.
Biosimilarity and Interchangeability
Waxman Proposed §262(k)(2),(3) &(5); Eshoo Proposed §262(k)(2)-(4)
Both bills will permit the FDA to license biologics that are “biosimilar” to an approved reference product. The Waxman Bill defines “biosimilar” as having “no clinically meaningful differences between the biological product and the reference product would be expected in terms of the safety, purity, and potency if treatment were to be initiated with the biological product instead of the reference product.” To establish biosimilarity, both bills require generic applicants to submit information showing that any biogeneric is highly similar in molecular structure to the reference product. Moreover, both bills indicate that clinical studies may be required, although they would not be mandatory. The Eshoo Bill expressly requires an “assessment of immunogenicity” that would generally involve a clinical study. The FDA, however, would have authority to waive this requirement, but only if it issues a guidance with respect to the particular product class to which the biologic belongs.
Although both bills permit the marketing of biosimilar drugs, they also grant the FDA authority to determine that such biosimilar products are also “interchangeable.” Under the Waxman Bill’s definition, a biologic is “interchangeable” if “a patient can be switched one or more times between the reference product and the biological product without an expected increase in the risk of adverse effects.” Thus, the FDA may license the marketing of biologics that are biosimilar, but not interchangeable. Waxman Proposed §262(k)(5)(B)(ii).
The two bills propose considerably different exclusivities for the pioneer. The Waxman Bill is modeled after the pioneer exclusivities presently available for drugs approved under the Food, Drug & Cosmetic Act (FDCA) § 505. Thus, pioneers would receive five years of marketing exclusivity for a product that has not previously been approved and that is not highly similar to any previously approved drug. Waxman Proposed §262(k)(10)(A)(i). Three years of more limited exclusivity are available for supplemental applications that represent a “significant therapeutic advance” for a “significant new indication or subpopulation.” Waxman Proposed §262(k)(10)(A)(ii).
In contrast, the Eshoo Bill grants pioneers a minimum of twelve years of exclusivity for a new biologic. Eshoo Proposed §262(k)(7). This is extendable to 14 years, if during the first eight years of exclusivity, the pioneer obtains supplement approval for a new indication, provided that this would be “a significant improvement, compared to marketed products.”
An additional six months of exclusivity for pediatric studies is also available under the Eshoo Bill. Similarly, the Waxman Bill permits between three to six months of additional exclusivity for supplements that provide a significant therapeutic advance.
The Waxman Bill grants a maximum of 180 days of exclusivity to the first biogeneric “to be approved as interchangeable.” This period, which runs from the first commercial marketing of the generic product, can be shortened if various triggering events tied to any underlying patent litigation occur. In contrast, the Eshoo Bill grants two years of exclusivity to the first applicant whose biogeneric is determined to be “interchangeable” with a particular reference product. Under the scheme proposed in both bills, generic exclusivity is not tied to challenging patents, and in addition, being first to file a biogeneric application does not provide any guarantee of exclusivity. Instead, it is the first applicant to qualify for “interchangeability” who is rewarded.
Furthermore, because both bills grant generic exclusivity only for interchangeability, the FDA may approve additional biosimilars that reference the same product during the first generic’s exclusivity period. The biogeneric’s exclusivity only prevents the FDA from determining that any of these other biosimilars are “interchangeable.” Finally, the Waxman Bill includes a further provision prohibiting authorized generics from marketing during this exclusivity period.
The proposed patent measures differ substantially from those in §505 of the FDCA and from one another. Both proposals use a system of information exchanges between pioneer and generic applicants. In both proposals, the pioneer discloses patent information upon a request from the generic applicant, but is not required to formally list patents in the Orange Book or other equivalent compendium. The Eshoo Bill requires the generic to provide the pioneer with a copy of its licensure application and “a detailed description of the biosimilar product, its method of manufacture, and the materials used in the manufacture of the product.” The Eshoo Bill also gives third parties notice of the generic application and permits them to also notify the generic applicant of their patent rights.
Patent Certifications. The scheme proposed in the Waxman Bill permits, but does not require, generic applicants to make any certification as to the invalidity or non-infringement of patents of which they are notified. The Eshoo Bill, like the §505 ANDA process, does require that the generic applicant certify that they will not commence marketing until the patent expires or that the patent is not infringed, invalid, or unenforceable. In both cases, the patentee may bring a suit for patent infringement if the generic applicant makes a certification of non-infringement, invalidity, or unenforceability.
No 30 Month Stay for Patentees. Both bills also do away with the 30 month stay of FDA approval that is available under §505 if the pioneer brings suit against a party making a patent certification within 45 days. Under the Eshoo Bill, if the pioneer brings suit against the generic applicant, the FDA would be prohibited by statute from approving the biogeneric only if a court determines that the patent is infringed before the pioneer’s exclusivity period expires.
The Waxman Bill includes a provision that would circumscribe the ability of a patentee to get a permanent injunction so that it is only available where generic approval would cause “more than irrecoverable economic loss, and … also will threaten imminent destruction of such person’s business.” Thus, patent litigation commenced in connection with a biogeneric application would not necessarily delay approval and generic competition.
Waxman Proposed §262(k)(19); Eshoo Proposed §262(k)(9)
Both bills include other provisions as well. For example, the Waxman Bill contains measures to constrain the use of citizen petitions to delay or block biogeneric approval. Conversely, the Eshoo Bill includes a provision that emphasizes FDA guidance documents and permits the FDA to refuse to license a class of biologics based on “science and experience.”
Table: Comparison of H.R. 1427, H.R. 1548, and FDCA §505.
“No clinically meaningful differences.” Info showing “highly similar molecular structural features” also needed.
Based upon non-clinical studies and any necessary clinical studies or other safety studies. The need for any of these studies is at the FDA’s discretion.
Any clinical studies should be designed to avoid duplicative and unethical clinical testing.
“Highly similar to the reference product.”
Requires non-clinical studies and clinical studies, including an assessment of immunogenicity. The FDA may waive one or more of these requirements if they are unnecessary, but the clinical assessment of immunogenicity can only be waived if the FDA publishes a guidance supported by data.
Not applicable to biologics.
As to small molecule drugs, requires the same active ingredient, plus a showing of bioequivalence.
5 years for a new biologic, 3 years for a supplemental indication or subpopulation, with possible 6 month extensions.
Minimum of 12 years, up to 14.5 years.
5 years for a new chemical entity; 3 years for supplemental indication or subpopulation; 6 additional months for pediatric exclusivity.
180 days generally but potentially sooner based on the course of patent litigation, awarded to first product to be found interchangeable.
2 years awarded to first product to be found interchangeable.
180 days subject to forfeiture, awarded to the first to file an ANDA with a Paragraph IV certification.
Upon a request of a generic applicant at any time, pioneer must provide a notification of all relevant patents to which it has rights to.
After generic applicant discloses information about its product, pioneer discloses a list of relevant patents. Third parties may also provide notice of their patent rights.
FDA Orange Book.
Optional: Generic applicant may provide a notice that any patent disclosed by the pioneer is not infringed, invalid, or unenforceable. Pioneer may bring suit in 45 days if given such a notice.
Mandatory: At least one type of certification required for each identified patent. Pioneer/third party may bring suit within 60 days for certain benefits.
A bill to amend the Public Health Service Act to provide for the approval of biosimilars, and for other purposes.
Sponsor: Sen Gregg, Judd [NH] (introduced 5/24/2007)
Latest Major Action: 5/24/2007 Referred to Senate committee.
Status: Read twice and referred to the Committee on Health, Education, Labor, and Pensions.
Summary and Status
To amend the Public Health Service Act to establish a pathway for the licensure of biosimilar biological products, and for other purposes.
Sponsor: Rep Eshoo, Anna G. [CA-14] (introduced 3/13/2008) )
Latest Major Action: 4/14/2008 Referred to House subcommittee.
Status: Referred to the Subcommittee on Courts, the Internet, and Intellectual Property.
A bill to amend the Public Health Service Act to establish a pathway for the licensure of biosimilar biological products, to promote innovation in the life sciences, and for other purposes.
Sponsor: Sen Kennedy, Edward M. [MA] (introduced 6/26/2007)
Latest Major Action: 11/19/2008 Placed on Senate Legislative Calendar under General Orders. Calendar No. 1127.
To amend the Public Health Service Act to provide for the licensing of comparable and interchangeable biological products, and for other purposes.
Sponsor: Rep Waxman, Henry A. [CA-30] (introduced 2/14/2007)
Related Bills: S.623
Latest Major Action: 2/15/2007 Referred to House subcommittee.
Status: Referred to the Subcommittee on Health.
Related bill: S.623
A bill to amend the Public Health Service Act to provide for the licensing of comparable and interchangeable biological products, and for other purposes.
Sponsor: Sen Schumer, Charles E. [NY] (introduced 2/15/2007)
Related Bills: H.R.1038
Latest Major Action: 2/15/2007 Referred to Senate committee. Status: Read twice and referred to the Committee on Health, Education, Labor, and Pensions.
To amend the Public Health Service Act to provide for the approval of similar biological products, and for other purposes.
Sponsor: Rep Inslee, Jay [WA-1] (introduced 4/19/2007)
Latest Major Action: 4/20/2007 Referred to House subcommittee. Status: Referred to the Subcommittee on Health.