By Kate Cook, Greenleaf Health
*Editors note: Since the publication of this article, the U.S. House of Representatives moved to approve this bill on May 9, 2019. The Senate still has yet to rule on the bill.
On March 5, 2019, Representative Anna Eshoo (D-CA) introduced H.R. 1520, the “Purple Book Continuity Act of 2019.” The bill addresses the availability of information about approved biological products that may support the development of biosimilar products. It has five cosponsors in the House, drawn from both sides of the aisle, and was considered with five other bills by the House Energy and Commerce Committee on April 3, 2019. The Committee advanced the bill, along with five others, as a step toward addressing runaway drug pricing.
The Biologics Price Competition and Innovation Act (BPCIA) of 2009 added the biosimilar pathway in section 351(k) of the Public Health Service (PHS) Act, creating an approval pathway for biological products based on a demonstration that the product is “biosimilar” to a referenced biological product that was previously approved under PHS Act section 351(a). “Biosimilar” 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 differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.
On its own initiative, the FDA first published the Purple Book in 2014 – one year before the 2015 approval of the first biosimilar product. The Purple Book lists biological products, including biosimilar biological products, licensed by the FDA under 351(a) or 351(k) of the PHS Act. The Purple Book includes the date a biological product was licensed under 351(a) and indicates whether the FDA evaluated the 351(a) product for reference product exclusivity under section 351(k)(7) of the PHS Act. Reference product exclusivity determines when a biosimilar can be licensed based on a showing of biosimilarity to that “reference” biological product.
People perusing of the Purple Book will quickly note that the FDA has not made a determination of the date of first licensure for most 351(a) biological products listed, and the book provides limited information about when reference product exclusivity will expire for biological product licensed under section 351(a). On July 18, 2018, then-Commissioner Scott Gottlieb announced that the FDA would be updating the Purple Book based on the FDA’s evaluation of additional information that could be incorporated to give biosimilar product developers more information. That same month, FDA announced in the Biosimilars Action Plan that the FDA intended to enhance the Purple Book to include more information about approved biological products. The agency intends that an enhanced Purple Book would provide a modernized, interactive user experience, providing information about newly approved or withdrawn BLAs and about reference product exclusivity determinations.
This commitment is also incorporated into the user fee goals for the biosimilar program. For the five-year period from 2018 to 2022, the FDA has committed to update the Purple Book to include the BLA number, product name, proprietary name, date of licensure, interchangeable or biosimilar determination, and whether the BLA has been withdrawn. The FDA would update this information within 30 days after approval or withdrawal and provide the date of first licensure and the reference product exclusivity expiry date within 30 days of the FDA’s determination.
Recognizing that the Purple Book provides useful information to sponsors of biosimilar products — and that additional information may be even more useful -- H.R. 1520 would create new requirements. For the first time, the FDA would be required to publish the Purple Book — the document is now published entirely on the FDA’s own initiative.
The bill would also require the FDA to step into the world of patent listings for biological products. There would be new requirements for the Purple Book to list patent information under some circumstances, and the FDA would be required to report to Congress on the types of biological product patents that should be listed in the Purple Book. Imposition of requirements like these assumes that the FDA is in the best position to address the validity of patents applicable to biological products, although the agency does not claim to have expertise in patent law. The FDA may need to add new expertise and staff to fulfill this role, which could be a considerable drain on current agency resources.
Moreover, under the BPCIA, the FDA has no responsibility for gathering information about biological product patents, and the agency’s authority to license biosimilars is not linked to patent enforcement litigation. This is different from the laws governing generic and other follow-on drugs under New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs), which link the FDA’s approval authority in some instances to patent litigation. Those provisions have embroiled the FDA in litigation time and again, and changes to require biological product patent listing could embroil it in biological product patent litigation, another resource-intensive activity.
Finally, the bill contains another provision that would be difficult to implement and may actually restrict future innovation. Proposed section 351(k)(9)(A)(i)(III) would require the FDA to state in the Purple Book for each biological product licensed under 351(a) “whether in vitro or in vivo bioequivalence studies, or both such studies, are required for [biosimilar] applications filed under [351(k)] which will refer to the biological product published.” As a threshold matter, the reference to “bioequivalence studies” is misplaced, since a demonstration of “bioequivalence” is required for a generic drug, while a biosimilar is required to demonstrate “biosimilarity.”
Nor should the FDA be expected to state whether in vitro testing or in vivo testing, or both, would be required for licensing under 351(k). The answer will almost always be “it depends” — on the particular state of technology at a particular point in time, on the particular resources of the sponsor, and on a variety of other factors. Listing this information in the Purple Book could freeze a standard at a specific moment in time, thus impeding the development of new approaches based on new technology and creative thinking.
H.R. 1520 represents a laudable effort to build on the FDA’s initial work in establishing the Purple Book and supporting the development of biosimilars. However, efforts to address data standards for biosimilars or to include patent listings in the Purple Book are misplaced. It could take the FDA a long time to develop this information for an individual reference product. Once such information is added, it may swiftly become outdated. This could lead to a less accurate, less timely, and less reliable Purple Book.
About The Author:
Kate Cook is executive VP of drug and biological products at Greenleaf Health, Inc. She joined Greenleaf after a long career at the FDA, including 15 years in the Office of Chief Counsel, five years in the Office of the Center Director at the FDA’s Center for Biologics Evaluation and Research, and one and a half as associate director for regulations and policy at the FDA’s Center for Devices and Radiological Health. You can contact her at firstname.lastname@example.org.