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.

 

Is Physician Resistance to Biosimilars Dissipating?

We tend to think of challenges to uptake of approved and marketed biosimilars coming from three areas: (1) the reference product manufacturers, (2) the physicians, and (3) the patients. The patent mazes and rebating strategies characterize the first, and patient advocates’ questions about nonmedical switching describe the last. Physician resistance, however, seems to be on the wane.

I was pleasantly surprised by conversations with health system chief medical officers and medical group administrators speaking about biosimilar implementation and adoption at the annual meeting of the American Medical Group Association last week in Phoenix. If this is any indication, the iPhysician resistance to biosimilars decreasingnitial trepidation of US physicians in using biosimilars in treatment-naïve patients is melting away. Medical society endorsement of the effectiveness of biosimilars and promises of significant cost savings seem to be convincing arguments on physician side. Of course, switching of a reference medication for a biosimilar in a patient established on treatment with the reference product remains another story.

Some of the physicians came to learn about biosimilars rather than share their experiences. They may or may not have been aware of the extensive European experience with specific biosimilar agents and drug classes, but they were willing to accept that (1) if the Food and Drug Administration (FDA) had approved the biosimilar, they expect it to be safe and effective and (2) that extrapolation would not be an issue if FDA approved the label. The use of biosimilars for nonapproved indications would be left up to individual physicians (and payers’ prior authorization systems).

It was clear that the potential of biosimilars to save their patients money was of paramount importance. This may signal a changing view that issues regarding safety and efficacy of approved biosimilars will be preempted by the need to address economic needs in initial prescribing for new patients.

There is also an indication that large medical groups and some health systems are willing to leave the decision making to the Pharmacy and Therapeutics Committee. If the P&T Committee places the biosimilar on the formulary, and it is a savings for their new patients, the biosimilar will be used. That also means that biosimilar adoption at this level will be seriously aided by the use of lower cost-sharing tiers for biosimilars. In other words, a separate biosimilar tier that requires less copayment or coinsurance than the reference product could be a real boost to patient use.

In other biosimilar news…Michigan’s governor has signed legislation making it the 37th state to expand its pharmacy laws to allow interchangeable biosimilar substitution. Now if there were only an interchangeable biosimilar to substitute!

Coherus Biosciences announced that it believes that it will obtain FDA approval and commercial launch for its delayed pegfilgrastim biosimilar in the second half of 2018, along with European approval during the same timeframe.

Pfenex disclosed that it is seeking partners for its own pegfilgrastim biosimilar, in addition to its biosimilar candidate to Lucentis®. Its stock price has taken a steep jump in recent weeks, rising to over $6 a share (from $4) since the beginning of March.

Interchangeability: Another Challenging Perspective

Although the FDA has offered a pathway for the interchangeable designation, a recent presentation at the AMCP Nexus meeting shone a new light on some fairly important challenges posed by the interchangeable designation.

Edward Li, PharmD, MPH, Professor of Pharmacy, University of New England, Portland, Maine, raised the Web image 3well-trod issue of manufacturing drift—that over time, the reference product in particular is often subject to slight changes in structure that may be due to manufacturing changes, or other factors. This is an extremely important concept in biosimilars, as it highlights that these biologics can never be exact copies of the biologic drug. In fact, the originator biologic produced today cannot be expected to be exactly the same as the medication that was first approved 15 years ago. Although the structure may have changed subtly in these complex molecules, the clinical effects and outcomes have not materially changed. With interchangeability, Dr. Li said, “There should be no clinically meaningful differences,” in terms of safety, purity, and potency.

Once the FDA assigns the interchangeability designation to a prospective biosimilar or one that has already been marketed (and subsequent studies have provided FDA with the data to conclude that it is interchangeable with the originator), payers expect to be able to freely substitute this biosimilar for the originator at the point of dispensing—an expected boon to health plans and insurers, as well as the biosimilar maker.

However, what of the interchangeable biosimilar in the future? If manufacturing drift continues to occur over the course of time, the variation in the biosimilar and originator product will have introduced new subtle changes compared with that previously used in the approval process. “Differences may accumulate over time,” said Dr. Li, and hypothetically, these can lead to differences in safety and efficacy.” Does the biosimilar manufacturer need to prove interchangeability all over again, five years later? Is there a possibility that the biosimilar can be reduced back to the ranks of ordinary biosimilars?

These are important questions. Only after we have a biosimilar  designated as interchangeable will we be able to broach this question. However, it does perhaps give the reference drug maker a line of defense in sparing loss of marketshare.

Will Approval of an Interchangeable Biosimilar Mean that Others Are Inferior?

In terms of the biosimilar market and utilization, the US has been at least one full decade behind Europe in every respect but one. Yes, we have the EU beat in a game they avoided playing: The interchangeability gambit. The Europeans never defined interchangeability as a separate concept for biosimilars, thus leaving the individual countries to decide whether to allow unencumbered switching of biosimilars for their originator drugs.

As in other areas of biosimilar policy and regulation, the US started very slowly. Leah Christl, PhD, Associate Director for Therapeutic Biologics, OND Therapeutic Biologics and Biosimilars Team, Food and Drug Administration (FDA) stated last week at the Drug Industry Association’s annual meeting in Chicago that she expects the first interchangeable biosimilar to be approved within about 2 years. This is probably realistic, based on the timeline of the adoption of the agency’s interchangeability guidelines. Comments on the draft guidance are being read by the FDA at this time. Seven years after the passage of the legislation calling for the biosimilar approval pathway. If there were competitors in this game, we’d be desperately trying to catch up!

It seems unlikely that the FDA has any active 351(k) applications seeking the interchangeability designation, although Dr. Christl did not reveal whether this was the case. The application process is confidential; a submitted application is publicized only if the drug maker issues a press release on its ownDeck 1.png. It would seem premature to seek the interchangeability designation before the FDA’s own guidance on what the review entails is released. This may not prevent a biosimilar manufacturer that has already received approval from taking the quick step towards interchangeability, especially if they have conducted a series of switching studies that meet the FDA’s criteria (e.g., NOR-SWITCH).

Payers are chomping at the bit for an interchangeable product in the 36 states (and 3 pending) that have signed legislation allowing pharmacies to automatically substitute a biosimilar for an originator biologic.

Others have pointed out that the interchangeable biosimilar may be a boon to its manufacturer, but it may have negative effect on competitive markets. For example, a noninterchangeable infliximab may be considered by prescribers or patients somehow inferior to the interchangeable version, devaluing this biosimilar. On the other hand, the maker of “infliximab-int” could experience increased demand and boost prices (or avoid decreasing prices in the face of other noninterchangeable biosimilars coming to the market). And this may be justified. No one really knows the manufacturer’s incremental cost of achieving this designation, based on:

  • The cost of conducting additional switching studies
  • The potential cost of responding to FDA requirements for more data
  • The opportunity cost in marketing time, resulting from a delay in the application or approval

The race for a product with this extremely valuable designation drags on at a snail’s pace. I hope I’m still writing about it by the time someone reaches the finish line.

 

What Happens When Switching Among Biosimilars?

Late last year, I wrote about a biosimilar challenge that could be on the horizon. With the approval of the second infliximab biosimilar (infliximab-abda by Samsung Bioepis), that horizon is a lot closer. However, we are no closer to understanding how to address the issue.

When Renflexis™ is launched in October (it is unknown whether the US Supreme Court ruling that wiped away the 180-day postapproval waiting period will affect this), 3 noninterchangeable versions of infliximab will be available. Based on patient turnover in health plans, the following scenario will soon occur.

 

Lee 2
Image Copyright 2017 by Lee Fogel

Mr. Jones, a 39-year-old man with Crohn’s disease, works for a large self-funded employer. He has been taking Remicade®, the reference product, for some time. In January 2018, his employer decides to change its plan offerings. His new health plan does not cover Remicade, favoring Inflectra® (infliximab-dyyb) instead. He could seek a medical exception to continue on Remicade, but his new plan actually offers considerable incentives to switch, including significantly lower cost sharing. After discussing the situation with his doctor, he makes the change, and experiences much the same clinical results. In 2019, his employer makes another change in plan. And this plan covers Renflexis on the specialty tier but has Remicade available on the higher-cost nonpreferred specialty tier. He and his physician are unsure of the best move.

Keep in mind that it would be rare and probably makes little sense for a health plan to cover both biosimilars and the reference product. At some point, the plan will seek a contract that leverages marketshare. In the scenario above, at what point does the patient unduly risk the development of neutralizing or antidrug antibodies?

No data have been published on switches among 3 biosimilar products. These agents are not designated as interchangeable—though Pfizer’s Inflectra may be closest to it based on its NOR-SWITCH investigations; therefore, no one is truly confident of what might or might not occur with regard to efficacy or safety. I suspect it may be some time before switches among reference product, biosimilar A, biosimilar B, or even biosimilar C may be considered routine.

Patients receiving biologic products for serious chronic diseases may also be subject to case/care management. This is not a clean transition when changing health plans. The situation described above will likely happen in the near future with infliximab and possibly adalimumab (once the patent litigation is cleared). It would be a good idea for health plans and insurers to start reviewing their options now to ensure both patient safety and cost-effective decision making.

Interchangeability Guidance Released, FDA to Require Switching Studies

On January 10, the Food and Drug Administration (FDA) released its long-awaited draft guidance on the interchangeability standard for biosimilar manufacturing.

It’s been quite a while since we have been able to discuss progress on interchangeability, so as a reminder, the practical differentiator between a product designated as biosimilar versus interchangeable is that the latter “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”

Not surprisingly, the critical mandated addition in clinical studies of an interchangeable biosimilar is the conduct of a sufficient number of switching studies; that is, studies where patients are alternatively given the originator product, switched to the biosimilar, and possibly back to the originator, without any measurable risk to patient safety or efficacy. Or as the FDA puts it “the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.”

Interestingly, the FDA does restrict switching studies to between the biosimilar and the US-licensed reference product only (i.e., no EU versions with bridging studies). The reason is related to slight, nonclinically meaningful differences that may be introduced in the EU version that is not present in the US originator product.

The draft guidance is subject to a 60-day public comment period. For those interested in commenting on the guidance, they can visit https://s3.amazonaws.com/public-inspection.federalregister.gov/2017-01042.pdf for instructions.

Some of the Conflicting Concepts Around Interchangeability

At the Biosimilar Multistakeholder Summit, a closed meeting of 17 executives that was held November 30–December 2 in San Diego, organized by StrategiX, a number of important issues were raised regarding the daunting question of interchangeability. In this post, we’ll address how interchangeability was framed at the conference.

Although the Biologics Price Competition and Innovation Act (BPCIA) tried to apply the concept of interchangeability, used in the generic marketplace approval process, to the more complicated biologics arena, few expected a smooth translation. In fact, the US Food and Drug Administration (FDA) has tacitly acknowledged the difficulty, when they postponed the release of their all-important guidance on the topic until late 2017.

The concept of interchangeability, as it applies to biosimilars, is unique to the US; the regulatory concept does not exist in Europe, where switching of products is not expressly prohibited. We assume that the FDA will eventually approve interchangeability in 2 ways: (1) tighter prespecified equivalence margins than now seen with conventional biosimilar testing and (2) additional clinical studies. Although manufacturers may decide someday to spend the additional money to to prove the extreme similarity of their agent to the originator, it may not have the impact on marketplace uptake that one might expect. For example, if a biosimilar product without the interchangImage result for raising the bareability designation is already approved upon the launch of the new biosimilar, and it is already being switched at the point of prescription, by the clinicians themselves, based on payer coverage policies, then what does the new product bring to the table?

If safety is is important to gauging the interchangeability of the product, this ignores the levels of confidence gained with the 10-year global experience with biosimilars—a virtually spotless record that seems to contradict the notion that interchangeability is important.

Another very interesting and valid consideration involves a bit of reverse logic regarding the standard biosimilar approval process. The biosimilar manufacturer does everything required to prove that their product is equivalent in safety and efficacy compared with the originator product. No manufacturer seeks to demonstrate that their biosimilar is not interchangeable with the originator product. If it was deemed not interchangeable, the participants agreed, the molecule would not be able to pass the basic test for biosimilarity.

Actions taken by US payers (e.g., CVS Health, UnitedHealthcare, the Department of Veterans Affairs) to exclude coverage from originator products should compel the move towards switching by the physician’s pen, in the absence of FDA action on interchangeability. By the time an interchangeable product is approved by the FDA, we may likely have a couple of biosimilars being used in this way already.

Largest French Hospital System Decides on Infliximab Substitution

Although Celltrion and Pfizer’s Inflectra® was not approved as an interchangeable product to Remicade®, this will generally not matter to US payers when deciding the coverage of the product in patients who have not had anti-TNF treatment in the past. This is of even less importance to French prescribers, where the European Medicines Agency does not have a mandate to rule on the interchangeability of biosimilars. That means it’s entirely up to the health systems and physicians to decide this matter, including whether to allow substitution or switching.

The basic question is whether the evidence exists this biosimilar monoclonal antibody is close enough therapeutically to the innovator product to justify substitution. In a commentary, French physicians stated that substitution is a foregone conclusion in their country. There is a French law forbidding the practice of automatic therapeutic interchange, preventing systematic institution of the practice.

The biosimilar version of infliximab was approved in 2014, and as governments in the EU have generally not taken a stance on substitution, hospitals and other healthcare systems have addressed this issue, building a consensus based on the experience of the Assistance-Publique Hôpitaux de Paris (AP-HP) (this is the largest public hospital group in Europe, accounting for 22,000 beds and caring for 12 million patients). Unlike in the US, infliximab is administered in the hospital setting in France.assistance-publique-hôpitaux-de-paris-office

However, AP-HP does have its version of the typical US Pharmacy & Therapeutics Committee, called the Committee on Medicinal Products (COMED). This hospital system decided that COMED should decide for itself whether infliximab biosimilars yielded essentially equivalent outcomes and on substitution issues within its hospitals. Last year, it came to the conclusion that the two available biosimilars were substitutable for each other and the originator product.

Furthermore, COMED recommended that (1) “a vigorous post-approval surveillance (full traceability) of these products should be implemented in AP-HP” and (2) “physicians should be encouraged to take part in the registries that will be implemented by the medical disciplines concerned in the AP-HP.”

Back in the US, will payers make their own public statements on switching? This is unlikely, owing to the potential for negative press, but it could ease any concerns prescribers have in using biosimilars. Again, the choice of prescription, without an interchangeability designation, is still in the doctor’s hands. It will be largely up to them to speed adoption.