An Update From BBCIC: A Conversation With Cate Lockhart, Program Director—Part 2

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.

BBCIC Update
Cate Lockhart, PharmD, PhD

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 pBBCIC Updateurposes, 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

An Update From BBCIC: A Conversation With Cate Lockhart, Program Director—Part 1

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 first post of our two-part interview with Cate Lockhart, PharmD, PhD, we explore how the organization is moving beyond start-up mode and towards providing real-world evidence on the efficacy and safety of biosimilars.

BR&R: Cate, what experiences or interests brought you to the BBCIC?

BBCIC Update
Cate Lockhart, PharmD, PhD

CATE LOCKHART, PHARMD, PHD: I was working in a small biotech company in Seattle. I was the health economics department. As is often the case in small biotech companies, it was a department of one.

I came into this role at the BBCIC in January 2018. Prior to that I’d been working on a part-time consultant basis with my predecessor, Bernadette Eichelberger, who was the architect of this organization. I had been working with her for a year and one-half or so, and to some extent, I learned about the inner workings of the BBCIC before I jumped into this role.

But what was really attractive to me was that it bridges a lot of areas of research, reflecting a lot of my experience in pharmaceutics, health economics, and pharmacy. This was, in so many ways, the perfect job for me because it really does marry all of those elements.

 

WHAT MAKES THE BBCIC TICK?

BR&R: Can you give us a little bit of a background on the collective intelligence methodology that underlies BBCIC.

LOCKHART: Sure. One of the unique elements of the BBCIC is our governance structure and the framework under which we operate. It’s a consortium, which means we bring together multiple stakeholders from a variety of perspectives. We have organizations who are manufacturers, we have managed care organizations, we have payers, we have some other nonprofit and some patient-engagement organizations. All of whom come to the table together for the common goal of conducting this research into the safety and effectiveness of biosimilars and their reference biologics.

Part of the logic behind that is, first, it helps to reduce some of the bias or perceived bias inherent in some research. Our work is not beholden to any one company, because all of the resources are pooled. In fact, some of our participating organizations are direct competitors, all sitting at the same table. That helps increase the credibility of the research.

Second, it gives us the opportunity to draw on the very broad expertise of our participants to hopefully make the research questions and the results that come out of our work relevant to as broad an audience as possible.

Third, it maintains a very high level of transparency. We operate under a charter. We have a board of managing directors. We also have a planning board or steering committee. Each of our participating organizations has a seat on the planning board. We have a science committee to help drive the scientific direction. We have a communications committee, and then we have our research teams. Each of these roles is clearly delineated in our charter, which is a publicly available document. We don’t operate in a black box.

BR&R: The BBCIC’s process is based on an existing program—the FDA’s Sentinel program.

LOCKHART: That’s a good point. The BBCIC is not part of the Sentinel program, but we leverage the infrastructure that was developed for Sentinel. The FDA spent a lot of time and money developing their common data model and coordinating its data partners to display and report their data in a specific way, so we’re leveraging that. There was no need to reinvent the wheel.

One key difference, in my opinion, is although our capabilities are very similar to Sentinel’s, our mission is a bit different. For one thing, we really are focused on biosimilars and their reference biologics. In that way, it fills a gap that FDA simply doesn’t have the bandwidth to address.

BBCIC UpdateThe research that BBCIC does is proactive. The FDA tends to be reactive, investigating potential safety signals once they occur. That is, they may receive a signal through their safety reporting system, at which time they can activate Sentinel and investigate the safety signal further. Their primary purview is response to safety.

On the other hand, BBCIC is proactively looking at safety and effectiveness in a real-world setting. That differentiates us to some extent from the other existing organizations that are doing this sort of large-scale, multi-stakeholder, multi-data source, observational research.

 

CAN WE CAPTURE SIGNALS OF WANING EFFECTIVENESS?

BR&R: Monitoring biosimilars’ efficacy or effectiveness seems to be extremely important, particularly with all of the discussions that we’ve heard about lot-to-lot variations and the potential for manufacturing changes. This also applies to the reference biologics.

Can you provide an example, if you can, of how the process might actually identify efficacy changes or maybe decreasing potency?

LOCKHART: We’re going into this under the assumption that there will be no discernible difference, because that’s what we believe. These products have gone through the FDA review process, and we trust the FDA reviewers and their process.

Effectiveness is a challenging outcome to measure when you’re analyzing administrative claims alone. So to get a better picture, we may be interested in looking at different types of data sources. Part of our work is to understand those gaps in data to measure effectiveness and identify other data sources that can help fill in the picture.

Because of the scale of our data “network,” for lack of a better word, we can more easily identify rare events. We expect the safety signals or signs of effectiveness changes to be [hiding] in the data, so you need to have a very broad, diverse network of data to identify those signals. With BBCIC, we have that breadth of administrative claims data to help answer some of those questions.

BBCIC Update

BR&R: When using an administrative data set, can we somehow identify switching as a marker for waning effectiveness? Hypothetically, if patients with rheumatoid arthritis who were receiving a biosimilar for etanercept began switching more frequently over time to a biosimilar or reference biologic for adalimumab, for instance, could that potentially hint at decreasing effectiveness? I’m guessing that one would need a tremendous amount of data collected from the various participating institutions to validate that sort of trend.

LOCKHART: It’s true. Switching is an interesting topic, and we’ve devoted a fair bit of time to it. When you’re starting to do observational research with administrative claims, adding switching into the mix introduces some difficulties in analysis.

You’re right—you do need a lot of data in order to really evaluate any switching trends, and you need enough longitudinal data in order to evaluate any outcomes. When a patient switches from one biologic to a non-biologic, from one biologic to another with a different mechanism of action, or between a biosimilar and reference product, you need to have data covering sufficient time of exposure in order to identify an emerging signal. We’re looking into some of those questions today.

It’s hard to answer the question of why a patient switched therapies. It could be a clearly administrative reason: A certain payer made a drug formulary change and suddenly covers only the biosimilar and not the reference product. That’s easier to identify. In some diseases, like rheumatoid arthritis, patients are on a pretty circuitous trajectory anyway, and they do a lot of switching. It’s hard to tease out what outcomes are a result of a switch versus a result of the underlying disease. Those are some of the difficult questions that we have to wrap our heads around.

We’re also looking into some methodological questions and developing some best practices for how to examine switching, because it does introduce quite a bit of complexity. That said, the European experience has yielded a richer field of data because of their longer utilization of biosimilars. Their studies have not shown, in the literature I’ve seen, any differences in safety or efficacy based upon switching. But again, teasing out the nuances is challenging with any data source.

 

Part 2 and the conclusion of our interview with Dr. Lockhart will be published in an upcoming post. 

Real-World Evidence Shows Biosimilar Epoetin Outcomes as Good as the Originator

The erythropoiesis-stimulating agents (ESAs) are among the first biosimilars approved for use in Europe, a decade ago. As more real-world evidence accumulates on the comparable outcomes of several classes of biosimilars, support increases for their utilization abroad. This past week, researchers from Rome, using a real-time patient registry, have confirmed the safety and efficacy of biosimilar versions of erythropoiesis-stimulating agents (ESAs) compared with the originator product (epoetin-alpha).

Dr. Francesco Trotta, Department of Epidemiology, Lazio Regional Health Service, Rome, led a team of investigators who evaluated the use of ESAs in nearly 13,500 patients with chronic kidney disease or undergoing treatment for cancer in a region of Italy (total population, 6 million) over a 3-year period, assuming a 6-month course of the agents. They assessed all-cause mortality and need for blood transfusion and the incidence of major cardiovascular events and blood dyscrasia, which comprised a composite endpoint of effectiveness and safety.

The results of this study were published in BMJ Open. In comparing 3 ESA biosimilars (Abseamed®, Binocrit®, and Retacrit®) to the epoetin alpha originator drug (Eprex®), the researchers found that in patients with chronic kidney disease, the risk estimates for the effectiveness and safety measures were not significantly different. Using a composite outcome, the biosimilars demonstrated an adjusted hazard ratio of 1.02 compared with Eprex. The biosimilars were also compared with other ESAs, including darbapoetin alpha, epoetin beta, epoetin theta, and methoxypolyethyleneglycol-epoetin beta. Though not considered biosimilars to these agents, the epoetin alpha biosimilars recorded an adjusted hazard ratio of 1.09 compared with these other ESAs. For patients receiving oncology treatment, the biosimilars demonstrated a better hazard ratio for the all-cause mortality outcome (adjusted HR, 0.82), which was on the “margin of statistical significance.” In terms of the composite outcome, the biosimilars exhibited a slightly improved adjusted hazard ratio (0.91). Subgroup analysis revealed some minor differences in outcomes, but none that would alter a patient’s clinical approach.

The authors concluded, “In both settings, our findings are suggestive of no difference between biosimilars and originators on relevant effectiveness and safety outcomes measured during the follow-up period.”

These results should not be surprising based on the success (and proliferation) of the ESA class since 2007. The fact that a US version of epoetin alpha has not yet been approved is surprising: Pfizer’s Retacrit was submitted in 2014, with hopes of being the first biosimilar on the market, but a complete response letter from the FDA the following year short circuited this plan. No other epoetin biosimilar is on record as being filed for approval with the FDA at this time.