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In its updated draft
guidance, the FDA announced that it (1) has decided not to add a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.
In the absence of really big biosimilar stories with far-reaching implications, let’s start with some interesting bits on biosimilars to begin this week.
First, insulin maker Eli Lilly asked the Food and Drug
Administration a very interesting question, in comments
on the agency’s guidelines on transitional drugs. Lilly requested clarification
of the rules under which it might introduce an authorized brand of insulin
(that is, a lower-priced version of an existing insulin brand). The insulins
are one group of medicines that is scheduled to transition to regulation under
the Public Health Services Act in 2020, and thus be subject to formal biosimilar
Second, Boehringer Ingelheim, which received FDA approval to market its adalimumab biosimilar Cyltezo® in August 2017, received a positive ruling in its patent litigation case with AbbVie. A federal court judge ruled that AbbVie, which makes the originator product Humira® must turn over all papers related to the Humira patents. This may actually move the court case out of the discovery phase, according to Fierce Healthcare, and potentially closer to an actual, early biosimilar launch. Third, Health Canada has decided not to add a four-character suffix onto the names of its biosimilars and biologics. Instead, it will rely on its specific drug identification number as well as the nonproprietary names to identify medications being taken. This of course, contrasts with the FDA’s practice. The FDA is the only major advanced regulatory system that requires the use of a suffix to distinguish biosimilars and their reference products. And it is not used by providers.
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 talk at the GRx+Biosims 2018 meeting this month in Baltimore was about challenges, but extrapolation was not one of them. Biosimilar interchangeability was. That was not entirely surprising. In market research projects I’ve been involved with over the past year, payers and physicians in medical groups have broadly indicated that they’ve gotten past the extrapolation question. They are willing to accept the Food and Drug Administration’s (FDA’s) decisions on approval for indications for which clinical studies were not performed. In fact, some payers have noted a willingness to not discourage a biosimilar’s use for an indication for which the reference product was approved but the biosimilar was not. This, of course, assumes that it makes economic sense to do so. Many physicians still harbor concerns about switching therapy but not in treatment-naïve patients. In other words, if the payer prefers one product over another in a new patient, they would change their prescribing practices. In other words, they would not “rather fight than switch.”
Instead, the meeting, which was sponsored by the Association for Affordable Medicines and its Biosimilars Council, raised other questions, including the rationale behind the four-letter suffix and the complexities around biosimilar interchangeability.
Are Four-Letter Suffixes Needed?
Two greater questions were raised, one very practical and one theoretical one. The first involves the issue of the random (or sometimes not, as in -sndz) four-letter suffix, which is required for biosimilars in the US, but nowhere else in the world. Japan requires biosimilars to be designated with a standard “–bs” suffix. However, the European Medicines Agency does not utilize any suffixes and relies upon the international nonproprietary name (INN) for tracking purposes.
To make matters more complicated, the FDA intends to retroactively provide a suffix to all reference products as well, which no doubt will challenge billing and coding systems. The question is currently unanswered in the US as to whether interchangeable products will carry a unique suffix or share the same suffix as the reference product.
Hillel Cohen, PhD, Executive Director of Scientific Affairs for Sandoz, believes that these suffixes will not enhance the ability to track the use of biosimilars. Despite not using any special designations, “if you look at the European experience,” he said, “96% of safety reports have been made with proper attribution.” He pointed to the small database of biosimilar use accruing in the US. “Out of 65 safety reports registered so far, 62 came in with the brand name,” Dr. Cohen said. “None of the 65 reports were entered with the four-letter suffix.”
More on Biosimilar Interchangeability
Questions around biosimilar interchangeability still abound, partly because the FDA has not yet issued final guidelines around the approval process. Apart from the misconception that a product earning the FDA’s interchangeable stamp of approval is a “better” product than an ordinary biosimilar, two specific questions were explored, one of which is mind-boggling, the other merely frustrating.
The challenge extends from the expectation of lot-to-lot variation that occurs with biologic manufacturing. Assume that biosimilar A obtains FDA approval as an interchangeable medication, based on the switching studies against a reference product. As time passes, this manufacturing “drift” occurs. In a conversation with Dr. Cohen, he asked, “Is the biosimilar still interchangeable with the reference agent?” In other words, will the drug maker have to conduct more clinical switching studies to maintain this level of confidence, proving once again that the drug will provide equivalent outcomes in all patients compared with a reference product that is now also subtly different?
The second theoretical question arises from one I had discussed in an earlier post, the law of transitivity. If drug B is a biosimilar to infliximab, and drug C is approved as a biosimilar to infliximab, too, are drugs B and C biosimilars to each other? The answer, according to the FDA, would be no, because they have not be evaluated for physiochemical similarity to each other, only separately to the reference product. However, for payers, the answer is not so clear.
Dr. Cohen took that question one step further. If at some point in time, there are biosimilars A and D, both of which have been granted interchangeable status to adalimumab, are they interchangeable with each other? Again, the official answer would be no, because that is not how the testing was performed.
This brings up another intriguing question: if I’m living in a state that passed legislation allowing for automatic substitution of an interchangeable product, can a payer substitute interchangeable biosimilar A for interchangeable biosimilar D, if the former is the preferred product based on contracting? Technically, if the physician prescribed biosimilar D specifically, the pharmacy would not be able to substitute, without the doctor’s consent. The FDA has not designated biosimilars A and D as interchangeable for each other, only the reference product Humira®. The concept of biosimilar interchangeability is still, many years after passage of the BPCIA, an enigma.
Of course, based our situation in September 2018, this scenario is purely speculation, and will require multiple drug makers spending their R&D dollars to attain interchangeable status (to the same originator drug). That’s one reason why I like attending these conferences—they offer exposure to new, often confounding ideas!
Judging from the comments at the Academy of Managed Care Pharmacy’s (AMCP’s) annual meeting March 27–30 in Denver, there is some hope and expectation that the Trump Administration will review and possibly revoke the naming convention for biologics and biosimilars that was finalized just recently.
The Academy’s position on the naming convention has not changed, according to Mary Jo Carden, VP of Government and Pharmacy Affairs. She characterized the naming convention chosen by the Food and Drug Administration (FDA) as unnecessary and confusing. Therefore, AMCP is still in favor of using the government-approved name and international nonproprietary name to biosimilars (and no new suffixes to existing originator products). In previous comments to the FDA, the Academy wrote, “AMCP supports a biosimilar naming convention using the same INN that has proven safe and effective globally for small molecule drugs and for biological products in Europe, and therefore it should be the standard in the United States. Using the same INN for biosimilars would also alleviate the need for multiple product identifiers in biosimilar labeling and therefore eliminate the potential for confusion by health care providers and patients.”
Doug Long, MBA, VP of Industry Relations at QuintilesIMS, in answer to a question from the audience, said he “might mention it to Scott Gottlieb,” newly nominated FDA Commissioner, to revisit it after his confirmation. Especially in light of the present administration’s statements to streamline the drug approval process and improve public access to less-expensive medications, this would seem to make sense. Mr. Long also said that he had difficulty fathoming the reasons behind the decision making on biosimilar naming.
Drug consultant C. Douglas Monroe, RPh, MS, pointed out that there is hope. The Office of Management and Budget has asked the FDA to postpone implementation, and public comments from numerous organizations railed against the policy. Mr. Monroe cited publisher Wolters Kluwer as saying that the “…FDA’s proposed naming approach is a solution in search of a problem.” And several organizations, such as NCPDP and drug manufacturers, complained of the time and billions in cost of applying suffixes to all existing biologics.
Although it may be appealing for the Trump Administration to simply scrap the existing final guidance on naming. If they do not simply revert to the basic INN nomenclature for biologics, do we really want to start the entire process of considering a new system from scratch again?