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!

Lessons From a New Report: Do More Biosimilar Approvals Necessarily Mean Greater Access to Biologics?

By 2025, biosimilars may well fulfill their potential in the US, and we will be awash in biosimilars approved by the Food and Drug Administration, which have cleared patent issues through expiration, settlement, or litigation. Beyond meaning that we will finally have several adalimumab biosimilars on the market and perhaps even an approved pegfilgrastim biosimilar, access to biosimilars will almost certainly be widespread at that time.

Biosimilar concept art.5-15-2017A new study from Avalere, funded by the Biosimilars Council, was released this week, and its principal finding is that by 2025, an additional 1.2 million US patients could gain access to biologics owing to the availability of biosimilars. The implication is that current restrictions by private, Medicaid, and Medicare Advantage plans on the use of expensive biologics will be eased once less-expensive biosimilars come to the market and that lower costs will result in more patients being able to utilize biologics than before.

Although I’m not aware of any studies specifying the percentage of the insured population (public or private insurance) who do not have access to biologics, we do know a good deal about the way payers approach them in general. One of the greatest priorities of plans and insurers is to manage the specialty pharmaceutical category. The stated goal is to ensure that patients have access to appropriate therapy (not all therapy). The most common way to achieve this is through the use of stringent prior authorization criteria or step therapy. For noncancer biologics, virtually no payer or purchaser (including government and employers) would allow first-line access of a biologic without trials of conventional treatment first. This is done to limit costs of treatment as well as to mitigate the risk of adverse events.

Another routine mechanism for controlling costs of these agents is to leverage their net costs by offering preferred or exclusive coverage to one or two agents in a category. For patients in the US, this means that the vast majority of insured patients may have access to 2 or 3 anti-TNF agents, but not all of them. The introduction of lower-cost biosimilars may influence this, as it could be possible that payers include a wider choice of biologic medications once biosimilars for all of these products are available. The reference products may also benefit, in that the competition-driven lower costs may well allow for wider choice of medicines within a class.

It is questionable whether lower costs will permit the wholesale removal on restrictions of biologics in a category. Will a biologic be available for use as a first-line agent rather than a third-line agent? The major professional autoimmune disorder societies have not written clinical guidelines that urge biologics use far earlier. That is partly because each of these agents carries significant, serious risks, which cannot be minimized. They may occur infrequently, but they can be devastating in patients unfortunate enough to experience them.

In the Avalere report, researchers cite the European experience, in which “introduction of biosimilars led to an average increase in utilization, compared to the year prior to the biosimilar entrance, of 32%.” If that did occur in the US, it would be a boon to manufacturers.

They pointed to the lower costs being the primary driver of greater use. Gillian Woollett, MA, DPhil, Senior Vice President, Avalere Health, confirmed via Email that “[increased biosimilar availability] will disproportionately benefit women and low-income individuals. The assumption is two-fold: That biosimilar competition will lead to better access due to lower-cost products (either the biosimilar or reference biologic or both). Additionally, competition between biosimilars and their reference products is expected to improve tiering through placement on lower tiers, higher rates of coverage, earlier use, etc.”

Their results were based on an evaluation of seven blockbuster biologics in particular: adalimumab (Humira®), bevacizumab (Avastin®), etanercept (Enbrel®), infliximab (Remicade®), pegfilgrastim (Neulasta®), ranibizumab (Lucentis®), and rituximab (Rituxan®). All of these products are expected to be marketed by 2025, although patent litigation could, of course, change this scenario.

The present assumption is that a significant portion of nonoptimized utilization of biologics like Humira is due to high cost-sharing requirements. With the wider availability of biosimilars, special biosimilar tiers (with relatively lower cost sharing) may be a good bet in the future. Dr. Woollett stated, “While the analysis doesn’t specifically assume the increased utilization due to specific actions (we don’t ascribe X% better access to more biosimilars tiers, etc.), we do assume that payers respond with efforts to incent utilization of either the biosimilar or the reference biologic (depending on contracting) and that leads to better access.”

Biosimilar Industry Group Urges Congress to Address Part B Reimbursement

Reimbursement of biosimilars for Medicare Part B beneficiaries has long been an issue for biosimilar manufacturers. The Medicare Payment Commission recognized this problem in its own recommendations to Congress earlier this year, and the Centers for Medicare and Medicaid Services (CMS) asked for comments on its 2018 proposed payment policy.

The Biosimilars Council, in a letter to CMS, complained that instead of the current policy of using a single J code (and average sales price) for payment for noninterchangeable biosimilars (based on the same originator product), a unique code should be issued for each. Under the current policy, the Council argued, incentives for prescribing biosimilars are limited, which discourages the development of “a robust biosimilars market in the United States.”

In a press release, Christine Simmon, Executive Director of the Biosimilars Council, stated, “Shifting biosimilar reimbursement to unique codes will help facilitate the creation of a thriving market and greater, more affordable, patient access to these medicines. This is a critical opportunity for policy to have a positive impact on the future viability of the biosimilars market.”

A letter sent to CMS Administrator Seema Verma, signed by Citizens Against Government Waste, CVS Health, Express Scripts, FreedomWorks, National Association of Chain Drug Stores (NACDS), National Taxpayers Union, Pharmaceutical Care Management Association (PCMA), and Prime Therapeutics, stated “Under the current policy, all biosimilars for a single reference product are combined into a single ASP… This policy is a significant departure from how CMS treats other drugs in Part B, as no other blended codes exclude the original reference product from the blended code with its follow-on counterparts. The letter also asserted that the opportunity for expanded patient access to these innovative therapies, be fully realized,” only if the policy is changed.

 

An Eventful Week for Biosimilars

It has been an eventful week in the biosimilar world during a rather uneventful beginning to 2017. The next likely FDA decision on a biosimilar will not occur until reviews of Samsung Bioepis and Merck’s version of infliximab or Coherus Bioscience’s version of pegfilgrastim are completed sometime in the second quarter.

However, the biosimilar world is girding for the opening arguments April 26 in the Supreme Court’s hearings on the validity of the 180-day notification (exclusivity) period. To this end, the Biosimilar Council issued a lengthy amicus brief arguing cogently that Congress did not intend to provide 12.5 years of marketing exclusivity to biologic manufacturers. Several others have petitioned the court with similar arguments, including AARP and America’s Health Insurance Plan. In fact, I would be interested in reading an amicus brief in defense of the notification period.

The Biosimilar Council’s parent organization recognized an opportunity was opening wide, and decided to rename itself. The Generic Pharmaceutical Association is now officially the Association for Accessible Medicines.

The European Medicines Agency handed Celltrion the approval for the first biosimilar of an anticancer monoclonal antibody. Truxima™ is a biosimilar version of rituximab, which will compete against MabThera® (which is also marketed as Rituxan® in the US). Celltrion has partnered with Teva to market the biosimilar in the US, if and when the FDA approves the agent. Celltrion is yet to file for FDA approval. Two other monoclonal antibodies have been filed with the FDA for the direct treatment of cancer—trastuzumab (Mylan/Biocon) and bevacizumab (Amgen/Allergan), both of which are expected to yield FDA decisions in the latter half of 2017.

Finally, a study was published this week that highlighted the overall cost problem for the health care system—the price of cancer medications are persuading significant proportions of cancer survivors to skip their drugs or specifically request lower-cost alternatives. It is well known that cancer diagnoses are one of the most common reasons for medical bankruptcy. An earlier literature review of the financial implications of cancer reported that more than half of cancer survivors were in debt as a result of their cancer treatment, and roughly half of cancer survivors experienced some form of financial distress. These investigators stated that depending on the study, between 4% and 45% of these patients “did not adhere to recommended prescription medication because of cost.”