Tag: interchangeability

Biosimilar-to-Biosimilar Switching: The Data Say Its Fine

The question of interchangeability for biosimilars has haunted the US Food and Drug Administration since the promulgation of the Biologics Price Competition and Innovation Act of 2010. The FDA’s draft guidelines on interchangeability evolved very slowly, and the biosimilar industry had to work to (1) keep up with the guidelines as they gained clarity, (2) tirelessly wage war on misinformation as to what an interchangeable biosimilar actually represented, and (3) grasp the value of interchangeability as a for-profit enterprise and whether to charge forward with the necessary clinical trials.

In this column, we have often addressed the interchangeability designation, and how it may be perceived. Leaders in the industry, like Hillel P. Cohen, PhD, Executive Director, Scientific Affairs, Sandoz, have hammered home strong arguments that interchangeable biosimilars are not “better drugs” than their noninterchangeable brethren. They are simply subject to additional switching studies to confirm their clinical similarity to the reference product. That does not mean they are more similar to the reference product than a standard biosimilar.

At the 2021 DIA Biosimilars conference held virtually this week, Dr. Cohen restated logic that may be obvious but less often discussed: if two biosimilars are deemed highly similar to the same reference product, those two biosimilars, through the Law of Transitivity, should be highly similar to each other.

Though logical, the concept of biosimilar-to-biosimilar interchangeability is not acknowledged on a regulatory basis. However, the potential for biosimilar-to-biosimilar switching is undeniably real.

Biosimilar-to-Biosimilar Switching Likely to Occur

A large proportion of patients receiving chronic therapy with biologics will no doubt change health plans or insurers over time. This happens voluntarily (e.g., they may choose a lower-price plan from year to year) or involuntarily (i.e., their employer changes the plan offering from one year to the next). These plans utilize their own drug formularies. Considering the launch of perhaps eight adalimumab biosimilars in 2023, health plans will likely prefer different preferred adalimumab products, based on the contracting offers they receive or the characteristics of the biosimilar (e.g., citrate free, high-dose formulation, interchangeable). The same can be said for insulin products, infliximab, ranibizumab, and even chronically used oncology agents. Assuming that is the case, biosimilar-to-biosimilar switching may be somewhat common in 2025.

Is that an issue? Likely not, said Dr. Cohen. He believes that any immunogenicity concern is a hypothetical argument, “and no empiric evidence exists to support the concern. Furthermore, no data has been published to support immunogenicity on a mechanistic basis.” The biosimilar is highly similar not only in efficacy and safety but also with regard to immunogenicity.

What the Data Say

Most of the available data on biosimilar switching comes from Europe, where biosimilars have accumulated over 2 billion patient treatment-days of exposure. Countries adopt whichever biosimilar has the lowest price, based on tendering systems. This may mean that more than one biosimilar is accepted, and these tenders can change from year to year. The regulatory concept of interchangeability does not exist in the EU, and switching may occur in both infusible as well as injectable agents.

Dr. Cohen pointed out that published studies of biosimilar-to-biosimilar switching, based on the European experience, amount to 12 trials, all of which used observational data. Two trials involved adalimumab, eight infliximab, one etanercept, and one involved rituximab. These totaled 1,223 patients. Additionally, 8 studies were reported as meeting abstracts, six of evaluated infliximab biosimilars, and one each for adalimumab and etanercept. Those trials totaled 1,295 patients. Although the studies varied in terms of their limitations and design rigor, they were consistent in finding no differences in patient clinical outcomes, immunogenicity, or pharmacokinetics and pharmacodynamics.

“From a scientific matter, we can trust biosimilar-to-biosimilar switching,” stated Dr. Cohen. “There have been no safety issues, and we’ll very likely have more (observational) data in upcoming years.” If the data continue to show no significant issues, “it would be reasonable to conclude that biosimilar to biosimilar switching does not have any clinical impact.”

Observational data will have to do here, as no biosimilar manufacturer would reasonably spend the money to conduct a randomized, controlled head-to-head trial with another biosimilar.

The Declining Value of Interchangeability Over Time

The inevitability of this discussion has a noteworthy effect: It lowers the value of an interchangeable designation over time. Consider the adalimumab situation, which is similar to one we posed a few years ago: A health plan decides to prefer biosimilar C, which is designed by FDA to be interchangeable to Humira®, around mid-2023. In doing so, the plan places an NDC block on the reference product, and moves to convert as many patients as possible to interchangeable biosimilar C. It achieves more than 80% conversion through substitution at the pharmacy or specialty pharmacy. However, the plan is offered a far better price in 2024 on biosimilar F, a noninterchangeable drug. Biosimilar C no longer has an interchangeability advantage. All of the patients who were converted from Humira were already converted. And biosimilar C is not considered interchangeable (by the FDA) with any approved biosimilar. Payers, however, will likely consider these agents freely switchable with each other, depending on how much weight the payer gives to citrate status and dose concentration characteristics of the products.

What does interchangeability mean in the realm of insulin products? We’ll delve into that rabbit hole in the next post.

Insulin Transitions: A Dead Zone in the Gap Year, and Other Considerations

An Assessment With Gillian Woollett, MA, DPhil, Senior Vice President, Avalere Health

In this two-part conversation with one of the real go-to experts in the biosimilar field and US regulatory process, we talk with Dr. Woollett about the upcoming transition for insulins and other pharmaceuticals in March 2020, when they become regulated as 351(k) biosimilars.

BR&R: Partners Mylan and Biocon recently received a second rejection for its insulin glargine follow-on product, because of the FDA’s inspection results of Biocon’s production facility in India. If they do not get approval by the FDA by March 2020, will they have to submit a new 351(k) biologic licensing agreement (BLA)?

Gillian Woollett, DPhil, MA: In all likelihood yes, but they can’t submit a BLA yet, because there is no reference product for comparison. I’ve been calling this period before March 23, 2020 the “dead zone” and after the “gap year.”

Gillian Woollett

BR&R: Is it possible, since we’re not talking about clinical deficiencies in the product’s data, that some sort of appeal process can be implemented to spare Mylan and Biocon from having to start the BLA process from scratch?

Woollett: We should not presuppose the nature of the deficiencies as any complete response letter is confidential to the sponsor. If the FDA’s concerns are answered by this coming March, there may be no delay. However, after is more of a challenge.

Even if a sponsor is able to submit a BLA on March 24, 2020, it will likely take FDA at least another year to review the application (the “gap year”). Most of the physiochemical and clinical data can be expected to be the same, at least, but this is still a lot of extra work. We likely won’t have an interchangeable insulin until the end of 2021 at the earliest. Hence, as outlined in our paper, this transitional process for insulin will delay competition, not enhance it. And that is a pity for a product as fully characterized as insulin, where we need competition to enhance access.

BR&R: Based on an analysis we did back in June, very few manufacturers have publicly disclosed an interest in producing a biosimilar insulin at the moment. Do you think prospective manufacturers have been discouraged by the transitional timeline?

Woollett: Even in Europe, I think they’ve struggled a bit. Maybe that’s related to the nature of the reimbursement in Europe.

If they are part of the “prequalification” for biologics being undertaken at the World Health Organization (WHO), many other things should be considered in getting global access to your insulin. The WHO’s prequalification effort, albeit limited to date to a pilot for rituximab and trastuzumab, may be particularly helpful to countries with limited drug regulatory capacity. My understanding is that insulins have not been added to the list, as a regulatory matter, but are being considered.

Under this prequalification, if a biosimilar (or other drug) was approved by an agency in a highly regulated market, then that product can go on the list. However, for inclusion on the WHO’s list, the drug also has to be launched—not simply approved. This was addressed specifically in March at the Medicines for Europe meeting in Amsterdam as a problem for biosimilars. The WHO is applying a hurdle over and above FDA approval, which strikes me as a little unnecessary and somewhat counterproductive.

Some companies have extensive experience with their insulin products, but it is not documented in the manner of the highly regulated markets. We hear a lot about real-world evidence in the US, but it is not really being accepted yet.

This is another area I believe the WHO should be going—setting the ceiling as well as the floor, because what we tend to do in the highly regulated markets is overdesign things. We tend to measure parameters, simply because we can (regardless of whether they matter clinically). I call it the “EPA problem”: You only have a contaminant in the environment when you can measure it.

FOUR-LETTER SUFFIXES IN THE TRANSITION

BR&R: Let’s talk about another instance of overdesign in our market, with insulin nomenclature and the transitional process.

Woollett: The FDA has indicated that they will not give these transitional products suffixes to their nonproprietary names. This is super important: The Agency apparently realized just how problematic and expensive changing the nonproprietary names to currently marketed products was going to be, and that they were being tracked adequately today. It would be a challenge to switch every database at midnight, throughout the supply chain, on the date of the transition to include the four-letter suffixes. This is a good decision and huge relief to many stakeholders.

The original draft guidance on nonproprietary names had the suffixes apply to approved biologics and biosimilars. The Federal Trade Commission (FTC) had made the case that having a suffix only for biosimilars flagged them as different, and anything that differentiates is necessarily a problem for competitiveness. This is what I call “friction” in the marketplace and will deter switches between reference and biosimilar products. By being fair, the suffix had to apply to all biologics, which raised the problem with the transitional products.

The databanks flagged the problem as a practical matter and massively expensive to reconcile. So, the FDA decided that drugs rolling over to the biosimilars would not receive suffixes. This will apply to all the transitional drugs—hyaluronidases, hormones, insulins, and somatropins, etc. All new products in these categories will get suffixes, irrespective of biosimilar or originator status. So “new” insulins, whether originator or biosimilar, will get suffixes, and this is going to be inordinately confusing, too, but not as expensive to implement.

Insulin biosimilars

BR&R: If they don’t apply a suffix to Basaglar®, for instance, and they do so for any transitional product approved after March 2020, it still undercuts the purpose of having the suffix—for identification of individual drugs.

Woollett: Agreed. It is evidence that you don’t need the suffixes in the first place. My overall objection to all of this is inconsistency. If you have a reason to do it, you’ve got to do whatever it is you’re doing for all products… and that is not what is happening.

INSULIN INTERCHANGEABILITY QUESTIONS

BR&R: Well, consistency has not been the FDA’s strong suit. And that goes for the interchangeability of insulins as well.

Woollett: Further, none of the products rolling over can ever be designated interchangeable, because they are not biosimilar in the first place, not even Basaglar.

BR&R: Exactly! Here’s the inevitable problem where the rubber meets the road: You’re a patient at a health plan. You have been receiving Lilly’s Humalog® to control your elevated blood glucose levels. Unfortunately, you need to switch health plans next year, and the new plan doesn’t cover Humalog. It covers Novolog® and excludes Humalog or offers it at a nonpreferred copayment tier. The health plan is not interested in whether these two insulin products are interchangeable from a regulatory standpoint. The same is true with the infliximabs and filgrastims.

Woollett: It has always been true that formularies change, but it is still the physician who is doing the prescribing, and so that is OK. For interchangeability, we are only talking about someone other than the original prescriber making the switch.

And by the way, for a biosimilars, it’s not that you are not interchangeable, it’s that you are not yet designated as interchangeable. People are saying that biosimilars are “not interchangeable,” but there’s no such thing. There’s only “designated as interchangeable.” The labels of all the currently approved biosimilars are silent on interchangeability.

BR&R: From a coverage or health plan standpoint, it doesn’t really matter to them.

Woollett: At the plan level, no. Presumably, the plan would just say, “Basaglar® is covered” and simply that there’s no coverage for Lantus®, the reference product for Basaglar®. Today, Basaglar® could be designated as therapeutically equivalent with no extra clinical studies. But after the rollover, Basaglar can never, ever be designated an interchangeable product that the pharmacist can automatically substitute, which seems crazy.

BR&R: Right. Something else that you’ve pointed out in many of your pieces is the problem that these products—outside of being delivered via syringe and needle—they almost always have unique pen-delivery systems. They are a combination of device and product. If you approve these combination products through the 351(k) pathway, will the FDA then have to consider the delivery device in the determination of biosimilarity?

Woollett: That was addressed, if you remember, with the first guidance on interchangeability. The Federal Register notice had two questions outside the draft guidance itself, and one was about human factors and included the devices and self-administration questions. The FDA apparently decided to keep those outside the interchangeability guidance itself, and that was wise. Nonetheless, many of the insulins are essentially combination products.

In part 2 of this interview with Dr. Woollett, we discuss her call for the FDA to move away from totality of evidence, and to “confirmation of sufficient likeness” in its evaluation of biosimilar BLAs.

A Payer’s Preference for Biosimilars, Interchangeability, and Incentivizing Providers to Use Biosimilars

In the last few weeks, we’ve seen a hail of biosimilars-related news, some of which significant, more having limited impact.

Building upon the success of its infliximab biosimilar uptake, Magellan Rx Management announced June 4 that it will extend its medical pharmacy program to the new oncology biosimilars (i.e., rituximab, trastuzumab, and bevacizumab) when launched. Magellan Rx had announced that its program saved 34% when it shifted utilization to infliximab biosimilars. This action was announced after UnitedHealthcare decided that it would prefer the reference biologic agents rather than the biosimilars starting in July, which caused much reaction.

In early May, the Food and Drug Administration (finally!) released its final guidance on interchangeability. Although there were no surprises in this document, it does lay out a definitive path for gaining an interchangeable designation. Other than Boehringer Ingelheim’s intention to seek the label for Cytelzo®, no other biosimilar manufacturer has publicly stated interchangeability as a goal. Boehringer cannot launch its biosimilar adalimumab, regardless of its interchangeability status until June 2023, so the strategic importance may be longer term. Switching biosimilars (for a reference product or for another biosimilar, with or without this designation) may be a more pressing question.

The Biosimilars Forum has launched an educational campaign on how aligning incentives in Medicare part B can save billions of dollars through the enhanced use of biosimilars. The industry group’s proposal includes using a shared savings model in which providers can receive savings bonuses when using lower-cost biosimilars. In addition, it is lobbying to increase provider reimbursement for prescribing biosimilars. This would be in the form of a greater percentage add-on rate in addition to the average sales price (ASP) paid for the therapy. These two actions could offset the current reimbursement disincentive, where providers bill higher amounts for prescribing higher cost (and likely higher rebate) drugs, currently at ASP + 6%. The organizations also call on the Center for Medicare and Medicaid Services to reduce patient out-of-pocket costs when a Part B biosimilar is used.

The Association of Affordable Medicines has also been focused on the issue of biosimilars in Part B medications, as well as on the potential implications of the US–Mexico–Canada Agreement. Passage of the agreement (still awaiting ratification on Capitol Hill) could have the unintended consequence of extending exclusivity for reference biologics; all other federal regulatory efforts are moving towards cutting delays in access to lower-cost biologics. The trade agreement therefore negatively affects the biosimilar industry, which frankly, cannot survive additional barriers erected in its path. The Association is hoping that harmonizing Mexico’s, Canada’s, and America’s biologic exclusivity period can be modified before the treaty is ratified.

When Biosimilars Are Switched for Each Other

In April, the Center for Biosimilars reported on a study of infliximab switching in patients with psoriasis. The researchers found no differences in safety or effectiveness in 24 patients taking infliximab biosimilars. I had to read the copy twice; it took me a couple of moments to understand the significance of this small study.

Beyond the disease state, the interesting part of this investigation is that the switch was not made between the reference product (Remicade®) and a biosimilar, but between two biosimilars (Inflectra® and Renflexis®). With today’s focus on the interchangeability guidelines and the well-publicized NOR-SWITCH studies, the potential questions around biosimilar to biosimilar switching is often overlooked.

biosimilar to biosimliar switching

As more biosimilars are approved and launched for several disease categories, this concept will prove to be as important as the reference biologic to biosimilar switch (or vice versa). The reason is simple: Coverages among plans will vary, and as patients change plans, they may need to change from one biologic version of the reference product to another. It is easy to visualize the scenario where Big Health Plan covers biosimilar A and City Health Plan covers biosimilar B, and patients changing plans every year or so might need to switch therapies. Then biosimilar to biosimilar switching becomes a common occurrence.

In 2019, this is not yet the new normal. Infliximab coverage is commonly limited to Remicade, and if a plan or insurer decides to cover another version of infliximab, payers usually choose one biosimilar to improve the deal they receive. Therefore, a patient changing insurers at the end of the year will most likely not have switch from one biosimilar to another (e.g., from Inflectra to Renflexis). They might, however, have to change from the innovator product to a preferred biosimilar.

For the other competitive, marketed biosimilar drug categories (filgrastim and pegfilgrastim), therapies are given less on a chronic basis, so the need for mid-regimen switching among biosimilars is pretty small.

When the FDA evaluates a biosimilar, it requires comparative physiochemical and pharmacokinetic analyses between that biologic and its reference agent. The FDA cannot find that two infliximab biosimilars are biosimilar to each other. That only stands to reason and the laws of transitivity. Yet, possible differences in immunogenicity, for instance, may cause some concern for physicians and patient groups. This has not been found to be a concern in Europe, where multiple biosimilars (including infliximab) have gained years of experience. Experience is also accumulating with another immunologic biosimilar, adalimumab, as multiple versions are widely in use since October 2018.

Payers may be less concerned, and for basic reasons: (1) they anticipate that FDA approval is sufficient proof of safety and efficacy, (2) they seek to cover the most cost-effective products, and (3) the scenario has not yet arisen to any degree. In the US, switching between biosimilars is still mainly a hypothetical problem.

The benefits of interchangeability in this case are hypothetical as well. One might expect that two adalimumab agents that are designated interchangeable to an innovator product would likely be associated with fewer fears of safety problems when switched with each other. To use a well worn cliche, we’ll cross that bridge when we come to it.

Boehringer Ingelheim Gives up the Fight, Signs AbbVie Agreement on Adalimumab

It seems that AbbVie has won the battle and the war. The last remaining holdout in the fight to bring a biosimilar adalimumab to market before 2023 has capitulated, as AbbVie announced May 14 that Boehringer Ingelheim agreed to the terms of a licensing arrangement. This agreement allows Boehringer Ingelheim to enter the marketplace July 1, 2023, getting a slight jump on some other licensees, but it effectively ends the protracted patent litigation that Boehringer hoped to win.

In an interview with BR&R, Molly Burich, Boehringer Ingelheim’s Director, Public Policy, Biosimilars and Pipeline, told us in October 2018, “We are committed to making Cyltezo® available to US patients as soon as possible and certainly before 2023.”

WHICH COMPANIES HAVE SIGNED LICENSING DEALS WITH ABBVIE?

Company/Partner Drug Name Launch Date
Amgen Amjevita* January 2023
Samsung Bioepis/Merck SB5 June 2023
Boehringer Ingelheim Cytelzo* July 2023
Mylan/Fujifilm Kyowa Kirin Biologics Hulio August 2023
Sandoz Hyrimoz* September 2023
Fresenius Kabi MSB11022 September 2023
Pfizer TBDNovember 2023
Momenta M923 December 2023
Coherus CH-1420 December 2023
*Received FDA Approval.

However, at that time, Ms. Burich also disclosed that Cyltezo would not be commercialized in Europe; in October, the stampede of biosimilar manufacturers had just left the starting gate. In addition, Boehringer had earlier decided to drop plans to develop other biosimilars in the pipeline and focus solely on Cyltezo. That would seem to leave Boehringer out in the cold until July 2023.

In response to BR&R’s query, Susan Holz, Boehringer’s Director of Communications, Specialty Care, provided the following statement: “As we previously shared, at this point in time, our focus remains on providing patient access to our biosimilar Cyltezo in the US, and future biosimilars activities will be driven out of this market. Boehringer Ingelheim continuously evaluates our business portfolio, and we assess potential strategic partnerships to help enhance our pipeline and development capabilities. As you know, we have stopped development activities for the rest of the world, and I am not able to comment on specifics regarding our biosimilar in- or out-licensing strategy.”

Boehringer Ingelheim had reported that it is seeking the interchangeability designation for its adalimumab biosimilar. In the possible scenario where Cyltezo won its patent challenge, and gained the interchangeability designation from the FDA (note that FDA only issued its final interchangeability guidelines draft this week), the marketing potential was rosy indeed. However, suppose the FDA approves the interchangeability label for Cyltezo. It cannot leverage it until after Amgen’s and Samsung Bioepis’ adalimumab biosimilars have launched. Will it have the same advantage? That’s difficult to say. Payers will be anxious to grab immediate savings on this product, and interchangeability may not be considered such a great benefit. That is, in four years, will payers routinely switch available biosimilar agents anyway? My guess is that health plans and insurers will be leaning in that direction.

On the other hand, it will be easier to automatically switch patients in nearly every state. That lever will only be used if Boehringer gives payers a real reason to use it—a significantly better deal than the existing options. AbbVie offered huge discounts (on the order of 80% in some countries) in an effort to hang on to some marketshare once biosimilars were available in the EU. After all, why worry about interchangeability and switching when you can continue to use Humira® at a 75% discount?

Ms. Holz told BR&R, “In regards to interchangeability, this is a very important issue for many stakeholders, as it is the catalyst for automatic substitution at the pharmacy level, which in turn may help drive efficient use of biosimilars and maximize the cost-saving potential of these important medicines.” She added, “We were very pleased to see the Agency finalized interchangeability guidance that retained the appropriate balance between a high-bar to prove interchangeability and product-specific flexibility to make such a status attainable.”

In the next four years, the price of Humira will undoubtedly rise. This will mean that savings gained in 2023 will be little more than money lost to the system over the previous 48 months. As significantly, it represents tens of billions of dollars into AbbVie’s bottom line from a product that was approved in the US 17 years ago.

Federal Policy and Biosimilars: A Conversation With Molly Burich, MS, Boehringer Ingelheim: Part 2

In part two and the conclusion of this interview, Molly Burich, MS, Director, Public Policy: Biosimilars and Pipeline, speaks to Boehringer Ingelheim’s progress in Cytelzo interchangeability studies, its plans for the product in Europe in the face of several adalimumab biosimilars launches in the EU, and also the complexity inherent in CMS’s plans to move biologic agents from part B to part D coverage.

Molly Burich, Boehringer Ingelheim
Molly Burich, MS

BR&R: Boehringer Ingelheim indicated that it started the study on Cytelzo interchangeability last year. What’s the progress on this effort?

Burich: The trial is continuing to progress. It’s a high bar and a big commitment. We will certainly publicize relevant information in due course.

We feel that for Cyltezo, in particular, interchangeability is an important component. It may drive switching. The study will also show a complement of clinical data around that topic. We hope to have information to share in the future. [Editor’s Note: The VOLTAIRE-X study, which will evaluate the effect of switching between Cyltezo and Humira in patients with plaque psoriasis, has an estimated primary study completion date of March 2020 and full study completion of July 2020, according to ClinicalTrials.gov]

BR&R: Speaking about Cyltezo, I have a question about the marketing floodgates being opened in the EU for adalimumab biosimilars. At least 4 are being launched in the EU after the October 16th patent expiration. Does Boehringer Ingelheim plan to join the fray?

Burich: Boehringer Ingelheim had planned to bring Cyltezo to patients in the EU. Due to the patent litigation with AbbVie in the US, we will not commercialize Cyltezo in the EU. Boehringer Ingelheim will continue all activities for our biosimilar in the United States. We are committed to making Cyltezo® available to U.S. patients as soon as possible and certainly before 2023.

PART B TO PART D TRANSITION BY CMS 

BR&R: Medicare has indicated that it will move many Medicare part B drugs into part D. To what extent will this affect biosimilar access and utilization?

Burich: It is a very hot topic these days. We have some pretty significant concerns on conceptually around what it means for moving from part B to part D. The key reason revolves around the access question, including patient cost sharing.

A move from part B to plan D could mean that patient cost sharing may jump significantly. We know that part B beneficiaries have wraparound or Medigap coverage to protect them from cost sharing issues. In part D, there is not such protection. Aside from the biosimilar question, the move from part B to part D really has to be explored and discussed a lot more to understand how we can ensure that patient access is not reduced through high cost sharing. That needs to be ironed out as it applies to any part B drug before we can speculate whether this is an opportunity for a biosimilar. Time will tell what that really looks like.

Last month, CMS released the Medicare Advantage guidance allowing for step therapy for part B drugs. That could be a potential opportunity for biosimilars, if we know how some of the access concerns will be addressed. We just don’t have the full picture at this point.

BR&R: Is it possible that this move to part D might spur some payers to create biosimilar tiers? These would require lower cost sharing for patients compared with reference biologics, assuming contracts with the reference manufacturer permits it.

Burich: In my opinion, we’ll need access to more biosimilars before we see a lot of that activity. It’s hard to foresee what big benefit design changes will be coming, but it’s certainly possible. We’ll need a mature market in the US before that will happen.

BR&R: The devil is in the details with this switching issue but there’s also an access issue. Plans can make midyear formulary changes, this would then apply to biosimilars and reference drugs covered under part D.

Burich: This is an important issue. The latest guidance that we saw from CMS, which is now a couple of years old, allowed positive formulary changes. Adding the biosimilar to a formulary is always allowed mid-year. The question involves removing an originator product or changing its tier.

CMS has said that those situations would be reviewed on a case-by-case basis. These rules preventing negative formulary changes midyear are there to protect patient access. It will take CMS some time to iron out what the process looks like for this type of potential formulary change midyear. For now, we’ll have to rely on CMS’s case-by-case review

BR&R: In general, payers do not consistently fund and manage self-injectable specialty drugs in the same way. In some cases, they cover these agents under the pharmacy benefits, medical benefit, or even both. Further, they can be managed under either benefit as well. However, it seems we are moving toward pharmacy management of these agents. How does this affect biosimilar access, if at all?

Burich: There will be more benefit design changes once we have a more robust biosimilar market. More specifically, when we have pharmacy benefit biosimilars.

We’ve mentioned CMS’s intention to move more of these products from part B to part D. It is possible that commercial plans will have different benefit designs and treat injectables differently than Medicare does. We want to make sure that biosimilar or not, the access piece is really at the center of those changes; it will not be beneficial to the biosimilar market if this move causes significant patient access issues (e.g., actual access to this drug or big swings in cost sharing). All of those things will be equally problematic for a biosimilar as they are for an originator, so we want to make sure we have our eye on the access component.

BR&R: Health and Human Services Secretary Azar and FDA Commissioner Gottlieb have loudly stated their desire to improve biosimilar patient and market access. The Biosimilar Action Plan was released earlier in the summer to that end. What is the one aspect of the Biosimilar Action Plan that appeals most to manufacturers like Boehringer Ingelheim?

Burich: The aspect of education, tackling both proactive education and countering misinformation is very critical from our perspective. We’d like to see more materials moving forward that focus on switching and on interchangeability. We haven’t really scratched the surface on those topics from an education standpoint.

The reality is that the FDA has an important voice and bringing validity to educational materials is so critical for patients, physicians, and health plans as well. We hope that the FDA will stand by its public commitment to release more reading materials, more videos, more web info, etc. It is especially important at this juncture; we are seeing misinformation and a lack of clarity on certain things.

IS THE BIOSIMILAR ACTION PLAN ACTIONABLE?

BR&R: One of the biggest barriers to biosimilar access is the patent thickets. The rebate trap problem is another story. What power does HHS have to clear out the patent thickets? Or is this an area that can only be addressed by Congress?

Burich: This is the most difficult part of the Action Plan, because it is unclear who can truly implement change and what change might be realistic. We have to protect true innovation that’s important to all stakeholders.

At the same time, there’s no question that patent litigation is the leading barrier to biosimilar accesss. Some makers of branded pharmaceuticals have constructed patent thickets so that they could sustain prolonged, expensive litigation against competitors, while stifling competition. Humira is the prime example: More than 15 years after the molecule was approved , no biosimilar is being marketed – in the U.S. What the answer is and which government agency can effect change has yet to be determined.

BR&R: That change won’t come quickly, in any case. Whether enacted by Congress or the Office of the Inspector General, which may have to reinterpret the safe harbor statutes, this may only first apply to the second-generation of biosimilar agents, beyond 2021 perhaps. It seems likely that this will be a very deliberate process.

Burich: I do believe Commissioner Gottlieb is thinking about both how to get more products launched in the short term and also the long-term vision of a sustainable biosimilar market. That is such an important part of the problem.

We were very happy that the FDA had their public hearing. The FDA panel asked a lot of thoughtful and probing questions to the individual speakers. We are fully supportive of the Action Plan and its individual components. If we saw all of those things come together and start to see action, including finalizing the interchangeability guidance and providing more education, the biosimilar market would be in a far better place.

BR&R: We say that biosimilar manufacturers can make their products attractive to payers, but payers need to play a positive role here. Commissioner Gottlieb has said that payers have to help in this process by taking the long-term view, by not automatically sticking with the reference product because of the rebate revenue. They have to be open to using the biosimilars and nurturing the health of the industry. Is there anything else the biosimilar manufacturer can do to convince payers to make this market viable?

Burich: Certainly, biosimilar manufacturers have to approach these payer negotiations and conversations with competitive and innovative contracting approaches. That does not just include pricing but also how do you drive volume and true savings to both payers and patients. That kind of innovative approach is necessary, because we know it’s a challenging market.

Biosimilar manufacturers have to look at the whole picture as well. That means providing targeted patient/physician services to really help ensure that the switching experience is seamless for the patient and the physician so that biosimilar utilization is not viewed as something very disruptive.

Word From the Adalimumab Front: A Conversation With Molly Burich, MS, Boehringer Ingelheim: Part 1

In the first portion of a two-part interview with Molly Burich, MS, Director, Public Policy: Biosimilars and Pipeline, Boehringer Ingelheim, we cover the challenges of driving biosimilar uptake, as well as the unique situation that has focused this manufacturer’s attention on biosimilars and interchangeability. 

BR&R: The viability of the US biosimilar industry is being challenged if companies cannot rely on revenue from switching, especially for the autoimmune category.

Molly Burich, Boehringer Ingelheim
Molly Burich, MS

Molly Burich: Yes, biosimilar uptake is certainly going to be dependent on switching. But switching comes in a few different types. One case involves patients who are going to be switched to a therapy with a different mechanism of action. Perhaps their existing therapy no longer works (or didn’t work in the first place).

Another case is medication substitution by the physician. The doctor drives that decision to switch the patient either to a biosimilar or to an interchangeable.

Lastly is automatic substitution, which will come as a result of interchangeability and enabled by state laws. However, that is only in play once a product gains the interchangeability designation.

All of those are important components, but certainly switching overall is an important part of the market viability.

BR&R: When we’re talking about automatic switching, multiple stakeholders are involved, including the prescribers, pharmacies, payers, patients. And none of it matters if we don’t have an interchangeable product or even final guidelines from the FDA on interchangeability. In retrospect, should we have made automatic switching for biosimilars based on something other than interchangeability?

Burich: There are a lot of stakeholders involved and this is. why multiple ways of switching will likely occur. In terms of switching, interchangeability allows pharmacists to switch one reference product prescription for an interchangeable one without intervention of the physician at the front end—pending state laws of course. The physician must be notified of the change.

In our opinion though, automatic switching is certainly not the only way to drive uptake of biosimilars. We believe physician-driven switching and payer-drive substitution via formulary decision-making are very important to drive the uptake of biosimilars.

BOEHRINGER INGELHEIM’S SINGULAR PRODUCT FOCUS

BR&R: Biosimilar utilization, and the overall market, has been growing slowly since the first biosimilar approval. Prospective biosimilar manufacturers have tended to jump into the market with both feet, filling their pipelines with multiple biosimilar agents. Boehringer Ingelheim may be the only major manufacturer with a single biosimilar listed on its pipeline web page. Is the company in a wait-and-see mode, to see if the industry will survive? Or is Boehringer making further investments in biosimilar development behind the scenes?

Burich: We are constantly in an evaluation process of our portfolio. Obviously, we are focused on our approved biosimilar Cyltezo® (adalimumab-adbm) and also on interchangeability, here in the U.S. That is our focus area. We believe that the introduction of biosimilars will improve the lives of patients, as well as contribute to the quality and economic sustainability of healthcare systems.

INTERCHANGEABILITY: MISUNDERSTOOD BUT NO SILVER BULLET

BR&R: The issues around interchangeability are particularly frustrating. At the time the BPCIA was written, was the concept of interchangeability (which does not exist in EMA regulations) an attempt to give prescribers and consumers a warm and fuzzy feeling of an AB-rated generic?

Burich: It’s an important question. As you said, when the BPCIA was written, interchangeability was viewed as a sort of silver bullet. The reality is that interchangeability is an important concept, but perhaps it makes more sense for only certain products. As we gain experience in the biosimilar market, we’re starting to see this.

We believe in the concept of interchangeability and in what the FDA has put forth about interchangeability. We do think there are questions about how an interchangeable product may be perceived compared with one that is not interchangeable. In our comments to the FDA, we encouraged the FDA to come out with educational materials that are geared toward talking about interchangeability, and talking about switching. These are all important questions and need to be addressed for the broad stakeholder community. The FDA is obviously best positioned to bring that type of education in the next round of materials they develop.

BR&R: We’ve heard a great deal about people mischaracterizing interchangeable products as being superior to biosimilars (for the same reference product). Why is this differentiation so important?

Burich: This issue speaks to education. All people engaging in the biosimilar space must realize that the designation of interchangeability does not mean it’s a higher-quality, safer, or more-efficacious product. It means that the manufacturer has conducted additional studies required by the FDA to enable that automatic substitution at the pharmacy level.

The FDA has issued clarifying pieces of information and education on their website about this, but there is room for more. The reality is that when a drug is approved as a biosimilar, it has attained the foundational designation proving that the drug is highly similar to the reference biologic, without any clinically meaningful differences. On the other hand, gaining the interchangeability designation is about conducting trials of multiple switches within the patient and expecting the same results in any given to patient. Those are two different distinctions. It proves something different, allowing for automatic substitution to occur.

In part two and the conclusion of this interview, which will be published in a separate post, Molly Burich speaks to Boehringer Ingelheim’s progress in Cytelzo’s interchangeability studies, its plans for the product in Europe in the face of several adalimumab biosimilars launches in the EU, and also the complexity inherent in CMS’s plans to move biologic agents from part B to part D coverage. 

More From GRx+Biosims on Four-Letter Suffixes and Biosimilar Interchangeability

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, Execubiosimilar interchangeabilitytive 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!

State Biosimilar Laws Need Clarity and Consistency

Although 41 states currently have passed legislation to enable plans to substitute interchangeable biosimilars, these state biosimilar laws seem an attempt to put the cart in front of the horse. Reginia Benjamin, JD, Director of Legislative Affairs, at the Academy of Managed Care Pharmacy, explained that the first state legislation to optimize the use of biosimilars was signed in 2013, before any were approved by the Food and Drug Administration.
Biosimilars Review Biosimilar ReportsMs. Benjamin’s presentation last week at the annual meeting of the AMCP in Boston highlighted the fact that by the time Zarxio®, the first biosimilar was approved, 10 states had similar laws on the books.

The individual state biosimilar laws do vary quite a bit. Some of them specified that notification must be given to the provider (via phone, fax, or notation in the EMR) that a reference product is being substituted. She added that these requirements are generally above and beyond what is mandated for the dispensing of other medications.

At the time the majority of these laws were enacted, the FDA had not yet defined the criteria for an interchangeable biosimilar.
As a result, the medications’ definition of interchangeability varies in some states’ legislation. For example, they may rely on the way the Biologics Price Competition and Innovation Act (BPCIA) framed interchangeability, which is less specific than the FDA’s current guidelines.

To complicate matters, said Ms. Benjamin, states may also refer to a level of therapeutic equivalence as defined by the FDA’s Orange Book. However, the Orange Book does not address biologics, only small molecules. The Purple Book would be the appropriate reference, but this was only introduced in 2014.

Additional state legislative language, which is not uniform, includes the following:

  • Patients must be notified before receiving the biosimilar medicine (and varying timeframes for such notification)
  • Receipt of patient approval of the interchanged biosimilar before dispensing
  • Requirements to state boards of pharmacy produce a website with information on FDA-approved interchangeable biosimilars
  • Limits on liability for pharmacists who substitute a biosimilar for a reference product (ie, no greater liability exists than for filling any other prescription)

Ms. Benjamin stated that “state laws are inconsistent with the intent of the BPCIA,” for instance, pharmacists do not have independent authority to substitute a biosimilar agent for the originator product without the approval of the health provider. They fail to recognize the Purple Book as the FDA’s reference source for information about the interchangeability of biosimilars.

She concluded that education is key in providing stakeholders to better inform them of the potential for these drugs, “to provide increased access to safe and more cost-effective drugs.”

Analyzing FDA Chief Gottlieb’s Remarks: One Challenge With no Easy Solution

Food and Drug Administration Commissioner Scott Gottlieb, MD, undoubtedly understands the threat to a successful biosimilar industry in the US, and his well-reported remarks emphasize some of the key issues. The policies that the FDA Commissioner wants to bring to bear on the multifaceted problem may be harder to implement. In this post, we examine one of those issues.

FDA Commissioner Scott GottliebIn the CNBC interview on Wednesday, he stated, “We’re taking a hard look at how we determine interchangeability so that we can make determinations that biosimilars can be used interchangeably with the brand of drugs.” Dr. Gottlieb correctly pointed out that the interchangeability question is complicated by “variants in lot-to-lot manufacturing of existing biologics and also a lot of variance in the products over time where there’s drift in the sort of formulation of the biologics that are currently on the market.” The variations that manufacturers of any biologics encounter create a “moving target” for not simply a manufacturer trying to prove biosimilarity but also interchangeability. He acknowledged that unexpected clinical effects of these variations have not yet been seen but the potential exists, which is why certain variations are subject to testing by the regulators to address the problem.

Yet, it is not practical to eliminate the lot-to-lot variation that has been seen for decades, sometimes incurred by plant changes or subtly different manufacturing techniques. Does this mean that biosimilar makers will have to test their agent against more samples of the originator biologic and in studies with more patients? For the purposes of proving interchangeability, the variation could undermine confidence in the outcome.

According to the FDA Commissioner, “We’re going to be putting out a set of policies to compel the branded drug makers who have biologics on the market to tighten up their manufacturing, to have less variance of their biologics that are currently on the market.” Preventing this variation in biologic manufacturing sounds like a costly (and possible futile) exercise. Let’s say for example, that one plant must be shut down for a time owing to maintenance; how does one prevent the manufacturer of a compound that demonstrates slightly different structural folding produced at another plant? Only an expert in biologic manufacturing techniques can answer this question.