Purple Book, brought out on September 9, 2014, by the FDA consolidates list of licensed biological products including biosimilar and their interchangeable biological products. This compendium guides pharmacists in implementing pharmacovigilance in biological products and its biosimilars. Biological products and biosimilars are FDA approved that are primarily governed under Public Health Services Act. For the FDA approval, a Biologics License Application (BLA) can be filed under sub-sections of Section 351(a) and 351(k) of PHSA. An application filed under Section 351(a) for biologics and innovator biologics should submit all requisite information supporting its safety and effectiveness. This section 351(a) application is also referred as a standalone application for its non-reliance placed on other biologic products. A BLA filed under Section 351(k) for biologics license should submit information that confirms the manufacturer’s claim that the biosimilarity of the product is based on data to animal studies, clinical studies and analytical studies. Thus, the primary purpose of the Purple Book is to enable cross-checking as to whether a licensed biological product under Section 351(k) is biosimilar to or interchangeable with the reference product and to provide information pertaining the exclusivity of such reference product. Thus, the Purple Book lists all the biological products licensed under Section 351(a) and lists correspondingly, all the licensed biosimilar and interchangeable products of the reference product.
Purple Book originally accommodated two separate lists:
- Biologics approved by FDA’s Centre for Drug Evaluation and Research
- Biologics approved by FDA’s Centre of Biologic Evaluation and Research
The aforementioned lists have been replaced and discontinued after FDA releasing a single, searchable, online database, Purple Book Database, storing all the information about FDA approved / licensed biological products. This planned transitioning to online database is a step forward for ensuring improved transparency and accessibility for patients, industry users and other stakeholders. The information of the biologic product listed in Purple Book include:
- BLA tracking number
- Product Name
- Biologic product’s non-proprietary name
- If a biological product is a biosimilar or interchangeable one
- Application number
- Approval date
- Biosimilar information
- Date of licensure
- Date of first licensure- this indicates whether the biological product qualifies for reference product exclusivity and the expiration date to such exclusivity if applicable.
- Expiration date of Reference product exclusivity (12 yrs)- This exclusivity period disallows FDA from approving a 351(k) application until the exclusivity period of reference product is expired in 12 years from its first licensure.
Biologics Price Competition and Innovation Act, 2009
BPCI Act of 2009 amended the PHSA Act to create an abbreviated approval pathway for biosimilars or interchangeable biological products, which is comparable to the one created through Hatch-Waxman Amendments for ANDA applications under FD&C Act for the Orange Book. BPCI Act requires the BLA applicant to submit evidences supporting the claim that the biological drug is biosimilar to reference product. Evidences should show that the drug has same dosage, same route of administration and same strength as the reference biological product, and additionally, exhibits no clinically meaningful differences in terms of its purity, safety and potency from the reference product. Now for the designation of interchangeability, the BLA applicant must provide requisite information to demonstrate bisoimilarity as well as to show that the biological product has same clinical result as its correspondent reference drug when administered to the patient. Moreover, it is essential to demonstrate that a biological product when administered to a patient more than once, the risks associated in terms of its safety and diminished efficacy upon alternating or switching the reference product with the biological product, should not be greater than the risks associated when administering the reference product alone.[1] Section 351(i)(3) of the PHS Act implicates that once a biological product has received the designation of interchangeability, it can be in official capacity be substituted for the reference product with no intervention from the public health care provider. [2]
PURPLE BOOK CONTINUITY ACT, 2020
Patent Listing in Purple Book
Since its time of outset, Purple Book limited itself in providing information on a biological product’s labeling of being a biosimilar or its interchangeability to a reference biological product, and accommodated no listing of patents for such biological products. However, with the recent enactment of Purple Book Continuity Act (PBCA), FDA has for the first time imposed the requirement of patent listing of approved biological products as well as FDA regulatory exclusivity information. This transparency of patent information facilitates the biosimilar developers in getting hold of the patent information before the patent dance itself. Patent dance is a procedural concept formulated under the legislation of Biologics Price Competition and Innovation Act, intended to create an opportunistic space for patent dispute resolution between biosimilar applicant and biologic license holder, thus facilitating for a less elaborative approval route for biosimilar applicants. The preliminary step that needed to be furthered for the patent dance is the disclosure of such patent information that could otherwise possibly result in infringement by the biosimilar applicant, as per Section 1(3)(a) of the BPCI Act. As per the new law, a window period of 30 days is provided for the biologic license holders to share the disclosed patent information and its expiry dates to FDA which would later be incorporated in Purple Book.
Section 325 of the Consolidation Appropriations Act has specifically recognized for biological product patent transparency which upon preliminary concordance with the Public Health Service Act, has given FDA a period of 180 days from the date of enactment of the Purple Book Database. Moreover, FDA is required to update the list within 30 days after its first publication to include newly licensed products. In regards to the patent information that has been already subjected to the disclosure during the patent dance, requires the reference product sponsor to submit such list of patents and its corresponding expiry dates before FDA, within 30 days after such disclosure to the biosimilar applicant. [3]When the exclusivity of the biologic product has been duly determined or established by the Secretary of FDA, the product would be accordingly fitted into the Purple Book.
Implications of the Patent Information Requirement in Purple Book
With the new law creating an attic for the incorporation of patent information alongside with other details of the biologic product, it is essential to understand its implications on a biosmilar applicant. As mentioned before, patent information gets incorporated in the Purple Book database only upon following a standardized disclosure of the same by the biologic license holder to the section 351 (k) applicant during patent dance. This implies that only subsequent applicants can have an effective perusal of the patent information mentioned in the Purple Book and little impact on the first applicant. It is imperative to understand that this patent information provided and updated in Purple Book is not holistic at its preliminary view since it is totally dependent on the extent of disclosure engaged in by the license holder during the patent dance. hence, when a subsequent applicant peruse through the provided patent information in Purple Book, the possibility of the applicant getting ambushed by the license holder with its unidentified patent information still lies ahead.
Exclusivity Information
Under the new legislation, FDA is required to codify all the regulatory exclusivities for biological products including any attached pediatric exclusivities.[4] Initially the list did not identify periods of orphan exclusivities of the biological products and their expiration dates, which are usually listed in Orphan Designated and/or Approved Products.[5] However, the revised Purple Book database has listed information on orphan exclusivities as well. [6]
CONCLUSION
Though biosimilar and interchangeable products are not as dominant in market place as the generic drugs in pharmaceutical sector, it is prospectively expected that the marketing of biological products will potentially increase. Even the enactment of Purple Continuity act can be viewed as a step taken towards this potential shift in pharmaceutical market. The confidentiality shield that once protected the patent information of the products are partially lifted with the new listing requirement under the Act. Essentially, this compendium is facilitated for the pharmacists in comprehending the nature of the biological product and its administration in patients, and to implement pharamacovigilance on the biological products.
Author: Vaishnavi Suresh, Symbiosis Law School, Pune
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[1] The “Deemed To Be a License” Provision of the BPCI Act Questions and Answers Guidance for Industry, https://www.fda.gov/media/135838/download
[2] Public Health Services Act, Section 351(i)(3)
[3] Consolidated Appropriations Act, Section 325 (a)(A)(iii).
[4] FDA/CDER SBIA CHRONICLES, November 18th, 2014, https://www.fda.gov/media/90150/download.
[5] Designating an Orphan Product: Drugs and Biological Products, https://www.fda.gov/industry/developing-products-rare-diseases-conditions/designating-orphan-product-drugs-and-biological-products
[6]Purple Book Database of Licensed Biological Products, https://purplebooksearch.fda.gov/downloads
