A statement by the Food and Drug Administration (FDA) departing
commissioner, Scott Gottlieb, reinforced a key aspect of biosimilar naming and
provided important updates to the use of four-digit suffixes for biologics and
In his statement, Dr. Gottlieb said, “In January 2017, the FDA
published a guidance document in which we sought to balance these concerns by
using a distinguishing suffix to the proper names of biological products,
including not just biosimilars, but originator products as well. By applying this
policy to originator and biosimilar products alike, the FDA sought to advance
the goal of patient safety—which the suffixes promote—without creating a
misimpression that products with such suffixes are somehow inferior to those
without. In addition, the FDA announced in that guidance that the agency was
considering the process to retrospectively change the names of biological
products already on the market, to begin adding distinguishable suffixes.”
In its updated draft
guidance, the FDA announced that it (1) has decided not to add a
4-digit suffix to biologics that have already been approved under the Public
Health Service Act, (2) transitioning products, such as growth hormone or
insulins, will not be given a 4-digit suffix, (3) the FDA will continue to
assign a suffix to biosimilar agents, and (4) any biosimilars that are
designated interchangeable will have the usual 4-digit suffix, which will be “devoid
of meaning.” In other words, the suffix will not distinguish an agent as
interchangeable from one that is not.
The guidance states, “FDA has determined that the core objectives of the naming convention—pharmacovigilance and safe use—can be accomplished by applying the naming convention to biological products 170 at the time they are licensed under section 351 of the PHS Act, and without applying it to licensed biological products that do not contain a suffix in their proper names. This approach is intended to minimize the potential burden for sponsors and the healthcare systems, and to avoid potential confusion for healthcare providers and patients, given that the nonproprietary names of drugs seldom change postapproval.”
The addition of a 4-letter suffix for new biologics is problematic, as the FDA had begun assigning them for at least a couple of years. So far, FDA has given 27 new originator biologics these unique designations, and it seems that to avoid even greater confusion, new biologics will continue to receive the suffixes.
The continuing use of the 4-letter suffix is controversial not only because of the reason stated by Dr. Gottlieb, but also because these designations have not been used to any significant extent in safety reporting. As stated here and in Biosimilar Development, these suffixes have been reported in fewer than 5% of all drug safety reports filed with the FDA to date (but without causing issues as to which biosimilar was associated with an individual report). The updated guidance reaffirms the FDA’s commitment to the use of these suffixes.
Dr. Gottlieb stated, “This framework will help secure pharmacovigilance so that the FDA can effectively monitor all biological products in the post market—originators and biosimilars—and promote patient safety. To aid in adverse event report tracking, originator, biosimilar and interchangeable products will have nonproprietary names that are distinct from each other.”
The problem with this frame of thought is that the suffixes will not achieve a greater level of security in terms of pharmacovigilance in practice. The suffixes are extremely difficult to recall: I know, I find myself today looking for references to nonproprietary names I’ve written about a hundred times. That is precisely why they will not generally be used in drug adverse event reporting.
The Biologics and Biosimilars Collective Intelligence Consortium (BBCIC) is the organization that will perform the critical task of postmarketing surveillance for biosimilars and their reference biologics. Started in 2015, the BBCIC is a nonprofit, scientific public service initiative, which partners with multiple stakeholders to accomplish its mission. In the conclusion of our two-part interview with Cate Lockhart, PharmD, PhD, we explore how BBCIC is communicating with its stakeholders and whether the FDA’s four-letter suffix for biosimilars will assist in its tracking efforts.
GETTING UP TO DATE WITH BBCIC ACTIVITIES
BR&R: Let’s talk a bit about what BBCIC is doing today. Can you give me an update on current BBCIC programs?
LOCKHART: Sure. We have completed our first round of descriptive analyses, composed of four studies that were designed to (1) characterize our patient population for these specific disease states and (2) understand our data. Can we reliably identify the cohorts of patients we’re interested in studying? Can we identify the outcomes that we’re interested in reliably? Do we trust our results, based on existing literature? What are the gaps in our capabilities? Those initial studies are completed, and we’re in the process of publishing those findings.
In the meantime, we have four work groups that are focused on methodological issues or filling in some of our data gaps. One group is working on best practices in comparative-effectiveness research (CER) methods. A lot of people are doing large-scale CER like this, but little consensus exists on best practices for performing it. We’ll come up with our own recommendations that will help guide our future research.
Another work group is specifically looking at switching patterns. The first phase of that work is completed. They identified methodological considerations for best approaching switching in the context of our research. We’ll soon be moving into the second phase, where we dig into BBCIC data and do a descriptive analysis, then we’ll start to understand the switching patterns in anti-inflammatory conditions, especially rheumatoid arthritis, and Crohn’s disease or ulcerative colitis.
BR&R: Will you be looking at switches from one biologic to another biologic? Or from one infliximab biosimilar to another?
LOCKHART: Well, that’s a good question. With rheumatoid arthritis, patients may change therapies many times and with different types of treatments. So we’re really looking at any and all of those. We are starting to get enough utilization of infliximab biosimilar products that we’re hopeful that we can start to include them in the analysis.
BR&R: When might we read some published data on some real-world evidence with biosimilars? Will it be in early 2019?
LOCKHART: It will take a bit longer. As everyone in the US has experienced, biosimilar uptake and utilization has been slower than expected. As we discussed before, in order to do robust research in this space, where we are looking at relatively rare outcomes—whether it is safety or effectiveness outcomes—we need enough utilization numbers in order to start that research.
We are in the process of initiating our first CER study in G-CSF products, because we believe we do have enough biosimilar utilization in that category to begin.
We have one project that’s looking at NDC and J-codes to evaluate how physician offices are coding their utilization of and administration of both the biosimilar products and their reference biologics. We’re just in the data analysis phase of that, so we do expect to see some publications coming out of that in 2019. We will be presenting five posters at AMCP Nexus in late October.
BR&R: One of the missions of BBCIC is to be transparent about what it is doing. Please tell me about the communication efforts of the organization.
LOCKHART: One of major efforts this year is to get the word out about BBCIC; too few people are aware of the work being done.
Part of that is because during the first couple of years, BBCIC, which was officially convened in 2015, was very much in a start-up phase. The organization was just getting off the ground and running. My role is to begin the transition from start-up phase into one with much more of a public face.
We’ve moved beyond this start-up phase. We’ve finished research projects. We’re starting to publish based on these projects. Personally, I’m accepting any speaking opportunity I can. I’m encouraging BBCIC participants to go to meetings and present. We are starting to get a little bit more traction in that respect.
Another effort is our quarterly newsletter, which very cleverly is called the BBCIC Quarterly. I’m producing the newsletter as a vehicle to keep the broader community—and our current participants—apprised of where we are in our research, our progress, our plans, and where we are publishing or presenting results. That newsletter is posted on BBCIC.org. Anybody who is interested in receiving the newsletter can contact me, and I’ll add them to the distribution list. I’m getting good feedback on it as a way to just keep people updated on the general goings-on.
BR&R: The outreach is really needed. During the course of FDA Advisory Committee meetings or conferences encouraging public comment, I’ve heard many times the mantra “we need to track the outcomes of these biosimilars” or “are we going to be doing postmarketing surveillance?” This gives the impression that there are no efforts underway to do just that.
THE FDA’S SUFFIX: FOUR LETTERS OR A FOUR-LETTER WORD?
Yet, BBCIC is focused on postmarketing surveillance. Now, part of the ability to conduct studies of biosimilars and their reference biologics involves another highly debated issue: the four-letter suffix. What is your opinion? Do we need four-letter suffixes of biosimilars and their reference biologics to track them?
LOCKHART: I see the value on both sides of this polarized debate. We’re doing our NDC and J-code exercise to look at how these drugs are ordinarily coded and whether the suffix is used. The reality is, usage is quite variable today.
On one hand, I agree that putting a suffix just on the biosimilar does put up a flag in people’s minds that there is something different about this product. We don’t do that with generic drugs, but certainly that there is a very different context between generic drugs and biosimilars. But the philosophy behind biosimilars and generics is really not that different.
For tracking purposes, there could be benefit in using the 4-letter suffix, but we can’t track it effectively if people are not using it for coding. And some of the coding systems being used today are not really designed to enter the suffix, so prescribers and administrative folks actually can’t code it in. There are some infrastructure challenges around that.
As much as I enjoy it when the government tells us to do things that are devoid of meaning, I personally believe that the use of random letters [in the suffix] makes it more confusing. I don’t remember what they are; the random suffixes are hard to remember, like –abda or -qbtx, with no meaningful context.
BR&R: At the recent AAM meeting, I heard Hillel Cohen from Sandoz say that of 69 adverse drug reports for filgrastim since 2015, all but four were filed without the four-letter suffix, and they were able to identify the correct brand, whether it was Zarxio®, Granix®, or Neupogen®.
It could be just as you said, that the administration system couldn’t handle the four-letter suffix, which is why it’s not entered. Or the providers ignored the four-letter suffix and used the INN and/or NDC code. Regardless, there doesn’t seem to be a rush to use the suffix in our early experience. Cate, from BBCIC’s perspective, is the suffix going to matter in terms of being able to track the use of a particular biosimilar?
LOCKHART: It’s really hard to predict. We’re in the position right now where infliximab is the only product where there’s more than one biosimilar on the market. If we’re looking at G-CSF agents, it’s not so complicated. It’s a hard question to answer, because it does rely so much on the infrastructure that we’re working with.
If we have these suffixes and nobody is using them, that’s missing the point. Some other countries don’t even bother with the suffixes—they just fill prescriptions with the brand name of the biosimilar. We still have a lot of inertia to overcome. Some of the controversy needs to be settled before we can even address the infrastructure problems.
From a BBCIC standpoint, I don’t think we know yet whether the use of the suffix will be critical, helpful, or neither. But, if providers or coders are not using the suffix in their claims, then it’s not helpful to us.
BR&R: Right. Well, it seems like pegfilgrastim may be the next test. We may have a second pegfilgrastim approval on or by November 3. That will mean two drug categories will have at least two biosimilars marketed. I’m guessing then it won’t be until into 2019 before we get a handle on who is using the four-letter suffixes for pegfilgrastim and who is not.
And the question of whether interchangeable products will get a unique identifier, no suffix, or something similar to the random four-letter suffix is still unanswered.
LOCKHART: That’s right. We still don’t know.
See Part 1 of our interview with Dr. Lockhart by clicking here.
The Food and Drug Administration’s final guidance on its naming policy for biosimilars has caused some stirring. Although it could never please everyone, the decision to require four-letter suffixes on biosimilars as well as existing biologic products does move the discussion forward.
Naming or renaming new and existing biosimilars is one thing. Renaming existing biologics is quite another. Those familiar with how pharmaceuticals are ordered, inventoried, and dispensed understand the scale of the information technology (IT) effort needed in terms of people and time. Don’t get me wrong, it can be done, but at a significant cost.
The first quantification of exactly what would be entailed in assigning suffixes to approved biologics was laid out by the American Society of Health-System Pharmacists (ASHP). In a February 13 letter to the Office of Management and Budget, ASHP stated the responsibility for updating IT systems would fall on public and private health plans and insurers. However, hospitals will also have quite a burden, including updating medication lists on their electronic medical records, scanning and labeling software, and revising pharmacy automation software and databases. In addition, the estimate points out the problem of having to discard medications that do not utilize the 4-letter suffix, assuming that the updated IT systems cannot identify both conventionally and newly labeled biologics.
The Society cited an estimate from the University of Utah Health Care’s Drug Information Service of approximately 40 hours per product. And this figure does not consider possible changes to pharmaceutical contract language. “All of this work would need to be accomplished using existing resources, thereby diverting human and financial capital that could otherwise be applied to clinical priorities. Conservatively, the dollar value of this work is thousands of dollars per each product,” according to ASHP. “With thousands of biologics currently on the market, extrapolating these costs across our healthcare system produces implementation cost estimates of, at minimum, tens of millions of dollars.“
Although FDA’s naming guidance for biosimilars has a basis in logic—to assist in identifying these biosimilars from each other and from the originator products, it is not at all clear that extending the use of meaningless four-letter suffixes to the originator agents is worth the effort. If infliximab is mentioned without a suffix, whereas its biosimilars are, does that not differentiate this agent? The assignment of a suffix to biosimilars only could save a significant amount of administrative resources, without loss of surveillance or tracking ability.
The news of FDA’s approval of Amgen’s Amjevita™, a biosimilar of adalimumab, was widely expected. It came late in the afternoon on September 23rd. Extrapolation for this agent was widely approved by the FDA, matching the indications for Abbvie’s Humira®. After all, it was the logical outcome after a 26-0 vote in July by the Arthritis Advisory Committee to recommend approval.
We may not see this product on the market for a very long time because of patent litigation, but I harbor a bit of hope that by the time of launch next year or even in 2020, the FDA will have chosen a reasonable rule for naming these biosimilars.
The nomenclature the FDA is using makes such little sense, but I I assume this to be temporary, The FDA has not yet released its final guidance on the matter. However, the horse left the barn months ago. Whatever FDA decides, they should have finalized it before approving 4 biosimilars.
So far, here are the FDA’s nonproprietary names, in order of approval:
Zarxio® — filgrastim-sndz (Sandoz)
Inflectra® — infliximab-dyyb (Celltrion/Pfizer)
Erelzi™ — etanercept-szzs (Sandoz)
And now: Amjevita™ — adalimumab-atto (Amgen)
Whereas -sndz is obvious, the rest are nonsense. I never thought I’d say this, but the strange, cobbled together syllables comprising brand names make as much sense as these suffixes. It would have been just as easy to provide somewhat reasonable designations. Not everything can be as basic as sndz, but even giving all of them alfa, beta, zeta designations could have indicated their order to the market.
At some point in time, the FDA will have to place its bets on one the red or black side of the roulette table and take heavy criticism from branded or biosimilar manufacturers, professional groups, and/or payers.
All that can be said today is that the agency seems set on a 4-character suffix, going so far as asking biosimilar manufacturers to contribute 10 preferred suffixes themselves (but even that suggestion was retracted by the agency).
Whether you approve of the suffixes or not, you probably agree that FDA ought to commit itself to one rule at this point. Whether that rule must be applied to all biologics (including reference products retroactively) is another, perhaps more perplexing, problem.