Late last week, the U.S. Food and Drug Administration released its latest Guidance for Industry relating to the biosimilar application process set forth in the Biologic Price Competition and Innovation Act of 2009 (BCPCIA). This Guidance, entitled Nonproprietary Naming of Biological Products, extends to both reference biologic drug products and their biosimilar counterparts. The basis for this naming regime, and its extension to both types of biologic drugs, reflects the agency's rationale for providing a naming convention in the first place and is based on FDA's dual responsibilities to protect the public and at the same time facilitate availability of biosimilar drugs according to Congress's intentions in passing the BPCIA.
In a nutshell, FDA sets forth a regime for a non-proprietary name that is the combination of a core name (equivalent to a generic name for small molecule drugs) combined with a four-letter suffix to designate its source. The suffix (both the requirement that each biologic drug have one and the "nonsense" ("devoid of any meaning") nature of it) has been the source of much of the criticism of the naming scheme since the agency published a proposed rule in the Federal Register of August 28, 2015 (80 Fed. Reg. 52224) ("Designation of Official Names and Proper Names for Certain Biological Products"). The Guidance provides its rationale for the proposed rule, stating that the naming scheme, which is required "for each originator biological product, related biological product, and biosimilar product," will "facilitate pharmacovigilance" (for all categories of biologic drugs), by permitting a specific biologic dug product to be tracked from its source particularly in instances where other means of doing so are not readily available. Also, these names would permit accurate source identification by patients, healthcare providers and payors (one of the features that biosimilar advocates fear might lead to discrimination). For the agency, using source suffixes also provides a means to "minimize inadvertent substitution" (especially when such biosimilar products, like all current biosimilar products have not been determined to be interchangeable; FDA will develop a naming convention based on the same principles for interchangeable biosimilar products but "is continuing to consider the appropriate format of the suffix for these products"). The benefits envisioned by FDA should "(1) encourage routine use of designated suffixes in ordering, prescribing, dispensing, recordkeeping, and pharmacovigilance practices and (2) avoid inaccurate perceptions of the safety and effectiveness of biological products based on their licensure pathway" according to the Guidance.
One aspect of the Guidance is that the naming convention will be used for all biologic drug products, both newly licensed as well as previously licensed drugs. For previously licensed biologic drugs (al of which are innovator-produced "reference biologic drug products") the revised proper (nonproprietary) name would comprise the original name as the core name and have a new distinguishing suffix configured consistent with the Guidance. While the process for implementing this "renaming" of previously licensed biologic drugs in ongoing, FDA will assign distinguishing suffixes to "a limited group" of these drugs as well as accepting submissions (presumably by the drug sponsor) for supplementing approved drug labels with new nonproprietary names include a proposed suffix. The names will be required for all "biological products licensed under the PHS Act, such as therapeutic protein products, vaccines, allergenic products, and blood derivatives, and [will] not include certain biological products that also meet the definition of a device in section 201(h) of the FD&C Act (21 U.S.C. 321(h)), such as in vitro reagents (e.g., antibody to hepatitis B surface antigen, blood grouping reagents, hepatitis C virus encoded antigen) and blood donor screening tests (e.g., HIV and hepatitis C)."
Returning to the agency's rationale for the proposed naming convention, the Guidance states that it anticipates "a growing number of biological products" to be entering the marketplace. The nonproprietary name (in contrast with the proprietary (brand) name, "reflects certain scientific characteristics of the product, such as chemical structure and pharmacological properties" and, inter alia, "helps health care providers identify the product's drug substance and distinguish biological products from one another." The proposed naming scheme was developed based on comments solicited by the agency from the public (as found in "Federal Register, 'Approval Pathway for Biosimilar and Interchangeable Biological Products; Public Hearing; Request for Comments' (75 FR 61497, October 5, 2010); 'Draft Guidances Relating to the Development of Biosimilar Products; Public Hearing; Request for Comments' (77 FR 12853, March 2, 2012); [and] 'Nonproprietary Naming of Biological Products; Draft Guidance for Industry; Availability' (80 FR 52296, August 28, 2015)"). The Guidance specifically recites that the naming convention is intended to "maximize the success of biosimilar products and interchangeable products and to help ensure the safety of patients receiving biological products licensed under the PHS Act."
The Guidance sets forth the "main considerations" used by the agency in arriving at the naming scheme. These include "enhancing biological product pharmacovigilance"; "ensuring safe use of biological products"; and "advancing appropriate practices and perceptions regarding biological products." With regard to pharmacovigilance, the Guidance acknowledges that despite agency efforts to "rigorously assess[]" for biologic (and other) drugs for safety and efficacy, issues can arise post-approval that create a need for the agency to be able to "track adverse events to a specific manufacturer" (or even specific lots or manufacturing sites) in a surveillance system that exists throughout the products lifecycle. If the source of a biologic product can be readily identified, remedial action can be taken effectively and not implicate products "for which no problem exists." Such surveillance systems can be active or passive, and can use identifiers including "proprietary name, proper name, manufacturer, national drug code (NDC) number, lot number, and billing codes." Unfortunately, many systems have "limited ability" to track products by manufacturer, according to the Guidance, and some identifiers are not recorded routinely (for example, in patient and billing records). The proposed naming convention is intended to "provide another critical tool for accurately identifying and facilitating pharmacovigilance for originator biological products, related biological products, and biosimilar products."
With regard to safety, the Guidance states that inadvertent substitution is a particular risk for biological products due to their complexity and "unique safety concerns related to immunogenicity." Inadvertent substitution, particularly wherein patients could receive reference biologic drug product and biosimilar versions thereof serendipitously, raises the specter of unapproved interchangeability, which the agency wishes to avoid until such time as it sets out the scope of what constitutes biosimilar drugs that can be considered interchangeable with the reference biologic drug product. There is also the risk of different versions of a biologic drug or biosimilar versions thereof to be approved for different indications, and the naming convention is believed to be helpful in ensuring that a drug be administered for just those indications for which it has been approved. There is also the risk that poorly informed healthcare providers or their patients might assume that a biosimilar drug having the same nonproprietary name as the reference biologic drug product had been approved as being interchangeable. This risk is mitigated not only by using distinguishable names but by providing in such names a ready distinction in the Purple Book (Purple Book: Lists of Licensed Biological Products With Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations).
Finally, the Guidance believes that by requiring routine use of nonproprietary names comprising source-identifying suffix in "ordering, prescribing, dispensing, recordkeeping, and pharmacovigilance practices" it will provide "a consistent, readily available and recognizable mechanism" for patients and healthcare providers to correctly identify the products (and their source) being administered). FDA also appreciates that by requiring both newly approved biosimilar drugs and previously approved reference biologic drug products to use the naming convention, "inaccurate perceptions" of the safety and efficacy of biosimilar drugs, compared with reference biologic drug products, can be avoided.
In practice, FDA intends to use the core name of a previously approved originator biologic drug for both the reference biologic drug product and all biosimilar versions. Source will be identified by a four-letter suffix otherwise "devoid of meaning." This naming scheme will indicate the relationship between the products (the core name) and identify source by the suffix. The agency also notes that having the distinguishing code as a suffix (instead of a prefix) will facilitate grouping the drugs together in electronic databases and thus help healthcare providers to locate their alternatives. Applicants for biologic drug products pending approval should propose to FDA up to 10 suffixes from which the agency could choose (and also submit any "supporting analyses" that could influence the agency's decision on the suffix to be used); current BLA holders for approved drugs and biosimilar applicants should do the same. Guidelines for suffix selection according to the Guidance should have the following characteristics:
The proposed suffix should:
• Be unique
• Be devoid of meaning
• Be four lowercase letters of which at least three are distinct
• Be nonproprietary
• Be attached to the core name with a hyphen
• Be free of legal barriers that would restrict its usage
The proposed suffix should not:
• Be false or misleading, such as by making misrepresentations with respect to safety or efficacy
• Include numerals and other symbols aside from the hyphen attaching the suffix to the core name
• Include abbreviations commonly used in clinical practice in a manner that may lead the suffix to be misinterpreted as another element on the prescription or order
• Contain or suggest any drug substance name or core name
• Look similar to or be capable of being mistaken for the name of a currently marketed product (e.g., should not increase the risk of confusion or medical errors with the product and/or other products in the clinical setting)
• Look similar to or otherwise connote the name of the license holder
• Be too similar to any other FDA-designated nonproprietary name suffix
The Guidance ends with the following statement of FDA policies regarding naming:
The final determination on the acceptability of a proposed suffix is based on FDA's review of all information and analyses described in this guidance, along with any information submitted by the sponsor.
FDA will evaluate proposed suffixes against the factors described in this section and may consider other factors if they impact the utility of the suffix in meeting the goals of the naming convention articulated in this guidance. Upon completion of the Agency's evaluation, FDA will notify applicants if a proposed suffix is acceptable or if all of the proposed suffixes are determined to be unacceptable. If all of the proposed suffixes are determined to be unacceptable, applicants may submit additional proposed suffixes for FDA's consideration. If an applicant does not submit a suffix that FDA finds acceptable or does not propose suffix candidates within an appropriate time frame to allow sufficient time for FDA review, FDA may elect to assign a four-letter suffix for inclusion in the proper name designated in the license at the time FDA approves the application.
And like all such Guidances, it contains an express disclaimer:
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page.
