U.S. BIOPHARMACOPEIA Registry of Biopharmaceutical Products (currently mostly discussion of Nomenclature and Terminology )

U.S. BIOPHARMACOPEIA Registry of Biopharmaceutical Products

FDA Biosimilars/Biopharmaceuticals Naming Proposal Fails on Basic Principles and Incoherency

By Ronald A. Rader, President
Biotechnology Information Institute

Abstract/Overview

The FDA proposed guidance is totally inadequate, technically terrible, including glaring omissions and continued use of legacy generic drug name conventions. FDA proposes to assign unique "proper" names to essentially all biopharmaceuticals/biologics, yet states nothing how this will be done! Based on the few biosimilars-related proposed names, FDA apparently plans to simplistically append a character string to "core" names, i.e., INNs (derived USANs). This is just further arbitrary jury-rigging of INN/USAN names, which were never designed for and are totally unsuited for biologics (as the years of debates about biosimilar nomenclature have made very clear). This may work to differentiate a few early biosimilars, but is an abysmal approach to naming biosimilars, much less all biologics, and is simply unsuited for U.S. needs and future applications! FDA for over a decade has been treating biosimilar/biologics nomenclature as a political problem, totally ignoring technical aspects -- and this shows. For example, FDA proposes no names for active agents (drug substances), leaving everyone to continue to follow legacy generic drug name conventions, with the active agent name and product (proper) name being the same, with 100% ambiguity! Irrationally, names are associated with BLAs, but BLAs are regulatory actions often with no relationship with what the products are, as entities (and isn't that what names should be assigned to?). And what will FDA do about the perhaps majority of biologics, those other than recombinant proteins, not covered by INN/USAN, including classic biologics, e.g., vaccines and blood/plasma products, and new classes of biologics, e.g., cellular and gene therapies, RNAi, individualized biologics, etc.? Worst of all, there is no mention of any process, any setting up of any nomenclature system,, meaning there is and will be none. This includes no information about the regulatory process, conventions/rules, priorities, etc. For example, who gets to propose, review and select the core and suffix names (FDA, INN, USAN, sponsors, industry input, public comments, etc.?). Also, there is no even mention of biosimilar/(bio)generic or class names; how new nomenclature will be disseminated/accessible; or names/identifiers reflecting "product drift." For about a decade this author has been predicting that FDA's approach to nomenclature would be a totally lame political compromise. That is what we got -- or worse, with the proposed names incoherent and a hazard to public health.

Introduction

The recent FDA proposed guidance concerning official non-proprietary (proper or established) names for biosimilars and all biopharmaceuticals fails, including on the basis of lack of coherency and consideration of the most basic (bio)pharmaceutical information principles and needs. Problems, further discussed below, include:

FDA proposes to assign unique "proper" names to essentially all biologics, not just a few biosimilars, yet tells us nothing about this. What system will be set up; what are the priorities for names; what are names to be based on, e.g., based on what products are (as entities) or regulations (as approvals); how this will be done and by whom; etc.?

From the proposed specific names provided, it appears that FDA plans to simplistically append a character string to INNs (derived USANs), further arbitrarily jury-rigging INN names, which were never designed for and are unsuited for biologics. This may work well enough to differentiate a few early biosimilars, but is an abysmal approach to (re)naming all biologics, and is simply unsuited for future applications. Technically and for many other reasons, this is just terrible. It took FDA over a decade of teams working on nomenclature, and this is what the agency comes up with!

There are no names for the active agents. with names for active agents never even mentioned. FDA apparently expects everyone to continue to follow legacy generic drug name conventions, with the active agent name and product (proper) name, being the same, with 100% ambiguity!

What names are based on is totally unstated, uncertain. Proposing a naming system without citing the basis for the names (i.e., the core product names) is simply incoherent, ridiculous. Names are apparently to be solely regulatory-based, assigned based upon granting of BLAs. But BLAs are arcane regulatory/legal constructs, not products. There is often with little or no relationship between what the products are, as entities, and their approvals. Also, BLAs (and thus, proper names) can be easily gamed by sponsors. If FDA is going to continue to use INNs (a worst-case option), it needs to tell us how and why that is relevant to U.S. biopharmaceutical nomenclature needs.

No information about any process, conventions/rules, priorities, etc. for these new proper names to be assigned to all biologics! For example, who gets to propose, review and select the core and suffix names (FDA, INN, USAN, sponsors, industry input, public comments, etc.?). And no mention of what the nomenclature conventions/rules and process will be. This is a totally new regulatory program, and FDA assigning unique proper names to all bioligics will have serious repercussions. Yet there is zero information about the naming process, both from regulatory/legal and information science perspectives. For example, FDA has not even proposed a name for these new names to be assigned to all biologics (what do we call them?; leaving everyone to use the generic term "proper names), and similarly no name/identity for for the related program to do this. This clearly indicates that FDA simply has and will not set up any actual process for new biologics proper names!

The proper names have no utility in the real world, i.e., other than for their designated prescription process-related uses. As noted by FDA, proper names are officially to be used for pharmaceutical "ordering, prescribing, dispensing, and recordkeeping practices." But what about everyone else and every other need for biopharmaceutical names? This includes industry, scientific/technical, medical and pharmacy communities, press and the general public too. Much as names for active agents are needed, product names actually usable for non-regulatory constrained/defined uses are sorely needed, such as product (and active agent) names based on what the product actually is, not arcane approvals.

What about biosimilar/(bio)generic names? Generic-type or class names are also needed for biosimilars (and all biopharmaceuticals), but there is no even mention of these.

What about names/identifiers reflecting "product drift?" Will FDA simply ignore developing any means to publicly disclose significant changes in approved products? Related to this, any naming approach that does not define what changes in marketed products require assignment of new proper names (what changes result in or define a new product) is totally useless.

Discussion

The proposed official proper name is to be formed from a core name, presumably the assigned INN/USAN (never stated), followed by a differentiating meaningless 4-letter suffix. This may be suitable (enough, for some uses/users) to differentiate some early biosimilar products, but what about the active agents? With FDA totally avoiding naming biopharmaceutical active agents, not even mentioning active agents names. with absolute certainty we can expect the same non-proprietary product (proper) names to continue to be used as the active agent name. This is the current paradigm, based on the legacy conventions used for many decades for generic drugs -- the non-proprietary active agent name is the same as the product name, i.e., with total ambiguity and imprecision (which suits generic drug interests well and need not be changed).

What about the active agent names? No naming system(s) has been proposed or even mentioned for biologics active agents/drug substances. In the absence of any guidance and without any alternatives, FDA and everyone else will surely continue with 100% ambiguity to use the generic drug names convention using the official non-proprietary product (proper) name as also the active agent name. Providing unique names for products, but absolutely no names for their active agents is incoherent, ridiculous, and a clear danger to public health (following much the same reasoning why FDA cites need for unique product/proper names). Product names without names for active agents/drug substances is totally inadequate, incoherent. How can FDA even properly function as a regulatory agency not having unique names/identifiers for biologic active agents/drug substances it regulates?

For example, the first approved biosimilar, trade name Zarxio from Sandoz/Novartis, was assigned filgrastim-sndz as its official current proper name (with the recent Fed. Reg. announcement proposing changing this suffix to a meaningless one, not an acronym for the sponsor). But what is the active agent? This simple straightforward question was posed to multiple appropriate public contact offices within FDA and Novartis, but all have refused to respond! Why, because the answer is outright embarrassing, something no one wants to admit. FDA (and thus, also the sponsor), as with generic drugs, including in Zarxio approval documents and labeling/insert, uses "filgrastim-sndz" as both the active agent and proper names. Or is the active agent name really "filgrastim," the worldwide recognized INN (with FDA inexplicably avoiding getting a USAN assigned for Zarxio)? Or is the active agent name granulocyte-colony stimulating factor, G-CSF, or other more descriptive, science-based name (but such names never even mentioned)?

Why is FDA seemingly fixated on using INNs (and derived USANs) as core names? Why use core names 1) from a nomenclature system developed many decades ago, back when viruses were considered filterable toxins and recombinant DNA was decades off? 2) from a system run by WHO/UN committees controlled by developing countries, with their primary interest seemingly being maximal generic names to support their own simplistic name-based interchangeability and 3) from a "system" that isn't even systematic or coherent in its handling biopharmaceuticals, that's too long been jury-rigged. Why would FDA want to uncritically use these poor quality, foreign-controlled names for the U.S. products it regulates? There are no laws requiring FDA to use INN-derived names for biologics, including biosimilars. Proper names for U.S. biologics should come from FDA or at least sources giving priority to U.S. needs.

Why is FDA even continuing to use INNs as "core" names? Besides their being unsuited for biologics, the core of the FDA proposal, the assigning of unique names to products. means totally abandoning the INN-based system (for biopharmaceuticals), something foreign countries and WHO will surely complain about. Keep in mind, this "system" involves core name selection by INN/WHO/UN, usually affirmation by USAN; and FDA then takes these names that are solely based on the active agents/drug substances and by government edict assigns these agent names to be official non-proprietary product (proper; established) names. Agent names arbitrarily adopted as product names; and then no name for the active agent! Looking to the future, how can FDA rationalize continuing doing this with biopharmaceuticals? It's simply unsafe -- products and active agents using the same name.

The FDA approach also violates the most basic chemical information principles -- that any unique chemical/product names/identifiers need to be a) unique, have a 1-to-1 correspondence with an entity (a suitable definition) and b) unambiguous. FDA's approach to unique proper names totally fails by both criteria.

What are these names assigned to? What are they based on? This is totally unclear, never stated. The proposal is a total failure based on this along. The FDA Federal Register Proposed Rule covering assignment of some specific product names associates names with each product's BLA. So, are names assigned based on BLAs, not anything at all involving the product itself? Currently, it appears that each BLA approval, past, present and future, results in a new proper name. But there is often little or no coherent correlation between products (as actual products, entities) and BLAs (arcane regulatory actions). Bottom line: Are names based on the product, what it is, or on BLAs/approvals; or on some unstated combination of both and maybe other aspects too? For example, if a new sponsor assumes marketing of a product and gets its own BLA (fairly common), do they get a new proper name (Is this the same or a new product, thus, getting a new name)?

Assigning names to BLAs, not the products, is simply inappropriate and inadequate. BLAs (and sBLAs) are a particularly poor choice as a basis for proper name assignment - there is often no coherent relationship between products (what they are) and their approvals; and BLAs are easily gamed. All it takes to get a new BLA for an already approved product is to make a change, any change, and file for a BLA. There are precedents for trivial changes resulting in new BLAs (with the products totally unchanged), such as approval of a new indication or a different company assuming marketing. At the other end of the spectrum, there are precedents for supplement approvals being granted for what, by any rational criteria, are totally new, different products. This includes a vaccine receiving sBLA approval for a switch from manufacture using a human to a monkey host cell line. Also, there are many precedents for products retaining the same proper name despite both a new BLA and significant changes in the product itself, such that most anyone would consider them new, different products (with sponsors often claiming these products are "new," even switching to new trade names). For example, there are precedents for products approved by supplemental BLAs containing human albumin as their formulation stabilizer being replaced by products containing sugars, e.g., sucrose, as their stabilizer, with these all retaining the same official name. Most would consider these new, different products requiring new proper names, if only for safety reasons. There are also multiple examples of biologics manufactured and marketed by one company but also marketed by other companies. For example, both Epogen from Amgen and Procrit from its licensee, Janssen/J&J, are the "same," with a single BLA granted to Amgen covering both. Will both products get their own or use the same proper names (as they currently do)? FDA provides no clue.

What about names for the new upcoming classes of biologics? And what about the 100s of biologics, perhaps even the majority of biologics (keeping in mind this includes blood/plasma, vaccines and other CBER-regulated biologics) that are currently fully interchangeable (in their product inserts). For example, even the CHO-cell and insect cells expressed recombinant hepatitis B vaccines are interchangeable, as are many or most other vaccines and blood products. FDA does not even mention how these - rather fixates on arbitrarily assigning a few biosimilars' names. FDA is clearly only thinking about interchangeability in terms of future biosimilar approvals, and is totally ignoring issues of naming the 100s of interchangeable biologics currently on the market.

There is no explanation of how names will be disseminated and accessible. What new databases will be developed and what information will these provide, in what forms? Will FDA lamely doctor-up the regulatory-constrained Purple Book to deliver names? But what about the names for great majority of biologics, including the 100s of other biopharmaceuticals/biologics currently marketed, much less legacy and future, products also to be given unique proper names?

What is the process (if there is/will be one)? Will there even be a nomenclature system or program? When a federal agency and, particularly, a regulatory agency doesn't even give a name or any identity to a program, this obviously means it's dead from the start. That is an unacceptable outcome for the U.S. biopharmaceutical industry and consumers.

Who actually gets to suggest, review and select the all-important core names, and what conventions/rules are followed? This is simply never even mentioned. And who actually gets to suggest, review and select the suffixes? This is totally unclear. The Federal Register notice vaguely cites sponsors up-front requesting suffixes. If so, what rules are there, such as can sponsors select 4-letter strings that are pronounceable, are brand-related, etc.? Will suffixes become trademarks?

Conclusions:

The FDA proposed guidance is totally inadequate, technically terrible, including glaring omissions and continued use of legacy generic drug name conventions. Minimally and rationally, if a unique proper name is to be designated for products, a name is also needed for the active agent. Continuing to use the same names for biopharmaceutical products and active agents is ridiculous and a danger to public health. Also, FDA needs to explain rules and criteria for proper and component core and suffix names, where the core names come from, who gets to provide input in core and suffix names selection, etc.

Otherwise, actual rationally-devised, coherent names, both unique and biosimilar/(bio)generic/class for active agents and finished biopharmaceutical products, are clearly needed. This author filed a Citizen Petition over 2 years ago requesting this, but FDA has yet to respond.

Further Information:

For further information about this and other aspects of biosimilar and biopharmaceutical nomenclature, visit www.biopharmacopeia.com. Or contact Mr. Rader at biotech@biopharma.com; phone 301-424-0255 (9-5, M-F).